Etiology and pathophysiology of the major affective disorders

Considerable progress has been made in identifying and characterizing the etiologic factors in major affective disorders, but a comprehensive and detailed understanding of the etiology of these disorders has yet to be achieved. Tremendous advances in knowledge during the past 20 years have provided excellent leads for focused scientific inquiry into the causes of these disorders; these leads, in turn, have led to the development of very specific and effective treatments. Like many other human diseases, the affective disorders are the result of interactions between the patient’s genetic makeup and the environment. Evidence continues to mount that significant genetic factors are involved in these disorders, but the genetic components do not appear to be so overwhelming that the disorder is manifested without any environmental challenges. In general, the causality of a major affective episode can effectively be conceptualized by using an interactional model of two intersecting continua both with progressive intensities. One involves the patient’s inherited constitutional predisposition to develop affective episodes; this interacts with the second continuum of the environmental stresses and life events to which the patient is exposed. Thus, there are those individuals with very high genetic predispositions for affective psychopathology in whom the disorder will be manifested seemingly without identifiable precipitating events. In contrast, there are patients with lower genetic predisposition in whom the disorder is manifested only when the patient is exposed to more serious precipitating life events and cumulative life stresses.

Genetic factors

Data derived from virtually every mйthodologie strategy in human genetics strongly suggest significant genetic influences in the major affective disorders, but as yet the mode of genetic transmission has not been established. The degree of genetic expression varies considerably from patient to patient and in some patients marked and predictable genetic factors are present; in others genetic expression appears to be significantly less influential. The twin studies have been one of the major research strategies used by psychiatric geneticists to attempt to quantify genetic loading in various psychiatric diseases. Twin studies in affective disorders have reported concordance rates among monozygotic (MZ) twins ranging from 33.3 to 75 percent, with an average of 65 percent. In contrast, the concordance rates for dizygotic (DZ) twins range from 9 to 23 percent, averaging 15 percent. The difference in concordance rates between MZ and DZ twins strongly suggests inherited genetic vulnerability. Further, there is evidence that even the polarity of the disorder may be genetically controlled, since there is an 80 percent concordance for bipolar and 59 percent concordance for unipolar disorders in MZ twins. In an attempt to separate the “nature” and “nurture” contributions to the development of affective disorders, the adoption study strategy has also been used. Unfortunately, because of mйthodologie problems and the paucity of subjects studied, no definitive answers are available. There is, however, a trend indicating that adoptees with affective disorders have a greater incidence of affective illness in their biologic parents than in their adopted parents. A large number of family studies have been conducted in the affective disorders. The standard paradigm is to make independent and blind diagnoses in the first-degree relatives of affective disorder patients, anticipating that if genetic components are present, the consanguineous relatives will manifest an increased risk for affective illness. First-degree relatives of bipolar patients have a morbidity risk for bipolar disorder ranging from 2.8 to 17.7 percent and a risk of 0 to 22.4 percent for unipolar depression. The first-degree relatives of unipolar patients have a risk of 6.4 to 17 percent for unipolar depression and of 0.3 to 29 percent for bipolar disorder. Thus, bipolar patients have both unipolar and bipolar disorders among their blood relatives, whereas unipolar patients have increased incidence for unipolar, but not bipolar, disorders in their relatives. Modern studies of genetic transmission combine careful family pedigree studies with molecular genetics in an attempt to identify the linkage between the specific gene markers and manifestation of major affective disorder in an afflicted or informative family. At present, no clear dominant or recessive inheritance pattern has been identified. It appears that genetic heterogeneity is present, which suggests a multiple threshold model in order to account for the varying degrees of genetic variability in the affective disorders. Genetic marker surveys in informative families have been conducted, including studies which have used genetically regulated markers that are etiologically significant in affective illness, such as the concentrations of dopamine B-hydroxylase, monoamine oxidase A, monoamine oxidase B, and lithium red blood cell (RBQ/plasma ratio. No marker has yet been found which segregates to the presence of affective disorder. There is however, a small subgroup of bipolar patients who do manifest a linkage of protan-deutan (red-green) color blindness and the Xg blood group with the presence of bipolar disorder. Unfortunately this very interesting genetic linkage pattern has not been present in other families similarly afflicted with major affective disorder.

In summary, the genetic studies strongly indicate the inheritance of a vulnerability to affective illness, but the genetic expression is heterogeneous and the degree of vulnerability varies significantly. There is evidence that the genetic factors are stronger in bipolar disorder than in unipolar depression. There are currently several large-scale surveys combining molecular and pedigree methodologies which are either in progress or in the final stages of implementation, and it is possible that the gene(s) coding for affective disorders will be identified and cloned in the foreseeable future.

Neurotransmitter systems

The most consistent search for etiologic mechanisms in the affective disorders has involved studies of the various neurotransmitter systems in the brain. The original biogenic amine hypothesis focused primarily on the central nervous system (CNS) neurotransmitters norepinephrine, serotonin, and dopamine, attributing depression and mania, respectively, to the deficiency or excess of these neurotransmitters at important synaptic sites in the brain. This hypothesis has stimulated and directed research in the field for many years, and data consistent with the hypothesis continue to emerge. Urinary and cerebrospinal fluid (CSF) studies of norepinephrine, its metabolite 3-methoxy-4-hydroxyphenethyleneglycol (MHPG), and the catalytic enzyme dopamine B-hydroxylase have been consistently reported as being increased or decreased in the predictable direction during depressed and manic episodes. More recently, increases in norepinephrine have been described in both mania and depression. Alterations in serotonin and its metabolites have also been identified in patients during depressive episodes. In addition, 5-hydroxyindole acetic acid (5HIAA), a serotonin metabolite, has been found to be reduced in the CSF of depressed patients who make frequent and aggressive suicide attempts. Deficits in other neurotransmitters such as dopamine and gamma-aminobutyric acid (GABA) have also been identified in some patients with major depression. Finally, another neurotransmitter hypothesis which has directed research in the affective disorders is the cholinergic hypothesis, which postulates increased central cholinergic tone in depression, decreased, cholinergic tone in mania, and an imbalance between the cholinergic and adrenergic neurotransmitter systems as being a central pathophysiologic mechanism in affective disorders.

Within the last 5 years, there has been a shift of research focus from the neurotransmitter biosynthetic, storage, and release mechanisms in the presynaptic neuron to the study of receptors on postsynaptic neurons. There is growing evidence that postsynaptic receptor kinetics and activity are predictibly and consistently altered during affective episodes and by the psychotropic medications known to ameliorate these disorders. Future research in the pathophysiology of the affective disorders will be concentrated on the role of postsynaptic receptor systems and the cascade of intraneuronal biochemical events in the postsynaptic neuron which follow the binding of the neurotransmitter to the receptor.

In summary, there is a general agreement in the large number of studies which have been conducted to date that the relative paucity of a neurotransmitter or the inactivation or down-regulation of postsynaptic receptors has often been correlated with depressive episodes, but the reciprocal changes which one would predict have not been consistently identified in manic episodes.

Environmental factors

There is little systematic data available indicating what role environmental stresses and untoward life events play or what types of stressors might be etiologically significant in the development of major affective episodes. Attempts have been made, for example, to relate early childhood loss and parental separation as predisposing factors for the future development of an affective illness, but the data are inconsistent. In general, studies have shown an overall temporal relationship between stressful and negative life events and the subsequent appearance of affective episodes. Research attempting to characterize qualitative differences in the impact of life stress have been disappointing, although serious life events such as the death of a child or a spouse, job loss, marked changes in social status, and even severe assaults on self-esteem have been linked to affective episodes. While the relationship between environmental stresses and the appearance of affective episodes has not always been demonstrated, generally speaking most experts agree that a single severe or multiple severe adverse events in life can interact with the constitutional predisposition of a patient and result in the triggering of an affective episode.

In further support of the influence of environmental events are the studies which have been conducted in higher primates. In these studies, phenomena which resemble or are analogous to the depressive states in humans are seen in monkeys following both mother/infant and peer separation paradigms. Furthermore, the monkey’s “despair” response to the separation paradigms can be predictably enhanced by drugs known to specifically alter central concentrations and metabolism of various relevant CNS neurotransmitters (e.g., norepinephrine, dopamine).

Biologic rhythms

The marked tendency of major affective disorders to periodic manifestation and possibly to seasonal variations has stimulated hypotheses which suggest that the dysregulation of biologic rhythms may be centrally involved in the pathophysiology of affective disorders. There are reports of dysynchronization of circadian rhythms in some bipolar patients in which these patients manifested both rapid free-running circadian rhythms (e.g., 23- versus 24-hour rhythms) and a phase delay in their rhythms. There is also a specific subgroup of patients with major depression in which the depressive episodes are manifested seasonally during the wintertime. These patients, while residing in more northern latitudes, experience major depressive episodes during the winter when days are significantly shorter and periods of darkness more prolonged; they do not experience depression of this type when residing in latitudes where the environmental light/ dark cycle is not as extreme.