The term ''bipolar disorder'' originally referred to manic-depressive illnesses characterized by both manic and depressive episodes. In recent years, the concept of bipolar disorder has been broadened to include subtypes with similar clinical courses, phenomenology, family histories and treatment responses. These subtypes are thought to form a continuum of disorders that, while differing in severity, are related. Readers are referred to the Diagnostic and Statisticial Manual of Mental Disorders of the American Psychiatric Association (DSM-IV) for details of this classification.
The diagnosis of mania is made on the basis of clinical history plus a mental state examination. Key features of mania include elevated, expansive or irritable mood accompanied by hyperactivity, pressure of speech, flight of ideas, grandiosity, hyposomnia and distractibility. Such episodes may alternate with severe depression, hence the term ''bipolar illness'', which is clinically similar to that seen in patients with ''unipolar depression''. In such cases, the mood can range from sadness to profound melancholia with feelings of guilt, anxiety, apprehension and suicidal ideation accompanied by anhedonia (lack of interest in work, food, sex, etc.).
Mania, manic-depression and depression, which comprise the affective disorders, are relatively common; it has been estimated that there is an incidence of at least 2% in most societies throughout the world. There is good evidence to suggest that genetic factors play a considerable role in predisposing a patient to an affective disorder. In a seminal Danish twin register study, in which the incidence of affective disorders was determined in all twins of the same sex born in Denmark between 1870 and 1920, a total of 110 pairs of twins were identified in which one or both had manic-depression. The concordance rates, that is the rate of coexistence of the disorder in twin pairs, for all types of affective disorder were found to be
Fundamentals of Psychopharmacology. Third Edition. By Brian E. Leonard © 2003 John Wiley & Sons, Ltd. ISBN 0 471 52178 7
47% for the mono- and 20% for the dizygotic twins. Further analysis showed that the discrepancy in concordance rates for manic-depression was even greater between the mono- and the dizygotic pairs, being 79% for the former and 25% for the latter. There was no difference in the concordance rate for bipolar and unipolar affective disorders in the dizygotic twins, the values being 24% and 19%, respectively. Such findings strongly suggest that affective disorders are inherited. Nevertheless, despite the apparent differences in the genetic loading for monopolar and bipolar affective illness, there is increasing evidence that both types of illness can be associated with the same genetic make-up. Thus a substantial portion of unipolar patients have the same genetic and biological vulnerability as bipolar patients. What causes some patients to display mania or hypomania whereas others do not is unknown.
More recently attempts have been made to define the mode of genetic transmission of affective disorders. A study of single autosomal locus markers in such patients has concluded that there is a lack of evidence to indicate single locus transmission, and that a polygenic model is more consistent with the available data. Linkage markers (e.g. the link between the X chromosome and colour blindness), autosomal markers such as those associated with human leucocyte antigen (HLA), and restriction fragment length polymorphism (RFLP) have also been studied in populations of patients with affective disorders. There was much excitement generated by the discovery that the RFLP analysis of the manic patients in the unique Amish population in Pennsylvania showed a link between the disorder and the insulin-ras-1 oncogene on chromosome 11. Unfortunately, a more detailed analysis of the data has failed to confirm these initial findings. At present it must be concluded that, while the heritability of manic-depression is evident from clinical studies, the mode of transmission and the identity of the transmitted defect have not been demonstrated. Nevertheless, with the spectacular developments in molecular genetics now taking place, one may expect considerable advances in the identification of the locus of inheritance to be made in the coming decade. Figure 8.1 illustrates the location of some of the genes implicated in bipolar disorder.
The various hypotheses that have been advanced regarding the biochemical cause of mania mainly centre on the idea that it is due to a relative excess of noradrenaline, and possibly dopamine, with deficits also arising in the availability of 5-hydroxytryptamine (5-HT) and acetylcholine. This simplistic view forms the basis of the amine theory of affective disorders regions iriifjIitaLed In bipolar d border
.region 4p marker D4S1 5S2
DRR5 gene (dopamine D5 receptor gens) marker D4S2949
U U li region 12q23-q24.1 the ATP2A2 gene region 12q22-24 marker L51251639
region 12q marker D12S342 D12S97
region 16fj region 21q22.3 homotagLie of drosphiia white gene.
tryptophan trani porter region 21q22 marker f'FKL D21S1260 D215263
region Xq 24-27,1
region J!q22_1 marker DXS67S9
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