The author expresses her appreciation to David Pauls, Ph.D., of the Depart­ment of Human Genetics of Yale University, New Haven, Connecticut, for his very useful methodological advice.
REFERENCES (more…)

Institute of Clinical Psychiatry, Milan Medical School, Ospedale S. Paolo, 20142 Milan, Italy
The linkage problem and linkage studies in recent years are a great focus in genetic research, because of their potential importance in giving us the oppor­tunity to better understand the inner genetic mechanisms at the chromosomal level, and thus allowing us to direct our attention to the hypothetical biological basis of the etiological processes of the disease. Segregation analysis may also give us reliable hypotheses about the genetic structure underlying affective dis­orders (10), but in any case the strongest evidence that they are primarily inherited (as opposed to culturally inherited), short of identifying a specific biochemical gene product, is to demonstrate genetic linkage to a well-defined marker (5). Ideally, the marker is itself an inherited characteristic that is polymorphic (i.e., it exists in two or more discrete forms that could be commonly found in the population), has a well-established and clearly understood mode of inheritance, is stable over time (not state dependent), is reliably detectable, and has been localized to a particular chromosomal region. Genetic linkage, then, is present when two or more loci are in close proximity on the same chromosome, so that genes residing at these loci fail to obey Mendel’s law of independent random assortment, and the degree of linkage is expressed in terms of recombination fraction (THETA). In a simplified way, THETA is a measure of the frequency that homologous chromosomes recombine in the region bounded by the two loci during meiosis. In this chapter we are particularly interested in the possible existence of a linkage between the Manic Depressive Illness (MDI) and the HLA system. The rationale of choosing the HLA system as a marker rests on two main points: (a) the HLA complex satisfies the requirements for a marker system probably better than any other potential marker (15), and (b) different investigators have suggested that one or more loci in the proximity of the HLA complex are capable of increasing susceptibility to affective disorders (13). There is at present a great debate about this point, and we will discuss later the effective role of the HLA complex in eliciting susceptibility to different diseases. (more…)

Overall these findings from the general practice study form quite a consistent picture with other emerging data. Rather than being selective drugs limited in their effect to endogenous depressives, the tricyclic antidepressants appear to be relatively broad spectrum drugs having true antidepressant effects over quite a wide range of depressive disorders. This includes neurotic depressives and anxiety depressives, and it extends much further than one might have thought into the mild range. It is only the very mildest depressives who fail to show drug/placebo differences. There may be limited differences in those who respond best based on symptom pattern, previous history, and other characteristics, but the general pattern is for tricyclic antidepressants to be of therapeutic benefit and to have a true antidepressant effect over a wide variety of patients, provided that they satisfy psychiatric criteria for depression. This applies clearly to anxious depres­sives and appears to extend well into the spectrum of anxiety disorders, although not necessarily to all such cases.

Center of Neuropharmacology, Institute of Pharmacological Sciences, University of Milan, 20133 Milan, Italy; and institute of Pharmacology, University of Pavia, 27100 Pavia, Italy
Benzodiazepines are the most wid ely used and prescribed pharmacological agents in the treatment of anxiety disorders. Although their exact mechanism of action is unknown, evidence has demonstrated the role of gamma-amino-butyric acid (GABA) in the anxiolytic, anticonvulsant, muscle relaxant, sedative-hypnotic effects elicited by these drugs (2,26). However, since the syndrome of anxiety encompasses a wide spectrum of symptoms, multiple biochemical sub­strates might be involved, especially when anxiety and depression coexist. In this report, the possible involvement of other neuronal systems, such as noradrenergic and serotonergic transmission, will be considered in the pathophysiology of anx­iety and depression. (more…)

Psychiatric Clinic, University of Pisa, 56100 Pisa, Italy; "Department of Psychology, Boston University, Boston, Massachusetts 02215
Although the efficacy of imipramine (IMI), phenelzine, and alprazolam in the treatment of panic disorder is well established (7,8,11-15), the usefulness of other members of the same drug classes remains to be proved. One aim of this comparative study was to ascertain whether a tricyclic antidepressant (TCA) with predominantly serotoninergic effects, such as clomipramine (CLO), had a different antipanic action from IMI. After more than 30 years as a standard comparative compound for clinical drug trials of antidepressants, IMI is currently the most widely used TCA for panic disorder. Although no drug has yet obtained an official antipanic indication in the United States, IMI has become the unofficial standard for comparison. In the last few years, several clinical studies have suggested that CLO also may be effective in the treatment of panic-agoraphobic disorders (2,4,5,10). Most of these were open and uncontrolled clinical trials that used CLO dosages lower than IMI. Other anecdotal information from personal communications with academic investigators supported these open trial findings. Moreover, CLO had been employed by us in the prior treatment of a group of panic-agoraphobic disorders, and we used comparable CLO and IMI dosages. Our findings were consistent with the reports cited in indicating CLO efficacy. Based on our findings and the other reports, we began to employ routinely both CLO and IMI as pharmacotherapies for panic-agoraphobic disorders en­countered in our clinical practice. We decided to randomly assign the drugs to patients with panic attacks used in our more formal double-blind clinical trials. As phenelzine is not available on the Italian market and alprazolam has become available only very recently, IMI and CLO were the two drug therapies most widely used in our practice. The CLO versus IMI study is still in progress, and this article reports a preliminary analysis of the findings to date. (more…)

Angela Orsini
Institute of Clinical Psychiatry, Milan Medical School, Ospedale S. Paolo, 20142 Milan, Italy (more…)