Mania presenting as an encephalopathy The manic patient may be disoriented and slightly agitated, with a clouded sensorium. This extreme is not frequently encountered but we have several times admitted patients to the neurology service with mania that presented in a manner suggesting an encephalopathy and global confusional state. The patient conducted himself pleasantly, without psychosis, pressured speech or overactive motor behavior but with an inattentive, confusion as the dominant feature. Conditions such as herpes encephalitis, alcohol or drug withdrawal, stroke, and paraneoplastic encephalitis were considered until the patient began filling notebooks with writing, manifesting insomnia, and making connections between ideas and events that were individually valid but just outside the realm of likelihood. One insisted that one of us was also his wife’s cardiologist and another, that one of the authors had scored a winning touchdown at a college football game at which he was present. Stories about public figures were factually correct but attached to the wrong person. The patient sat near the door to his hospital room and incessantly but pleasantly attracted our attention to speak to him every time one of us was in sight. At the same time, performance on orientation, arithmetic, and language tasks were normal. Such an individual is depicted in Reaching Down the Rabbit Hole by Ropper and Burrell.
The following are the main theories, not mutually exclusive, that have been proposed to explain the origin of depression; for a detailed review of the subject, the reader is referred to the review by Belmaker and Agam.
The capacity to experience sadness and depression is common to all people but there is no question that some individuals are more liable to depression than others who are subjected to similar psychosocial forces. It has been estimated, using various genetic techniques, that as much as 40 percent of the risk of depression is heritable (lower than for schizophrenia and bipolar disease). Adopted children whose biologic parents had affective disorder are at greater risk of developing this disease than are adoptees whose biologic parents were not affected (Mendlewicz and Rainer; Cadoret). The frequency of these illnesses is greatly increased in the relatives of affected patients (prevalence rate of 14 to 25 percent in first-degree relatives). Similarly, the risk of depression among first-degree relatives is increased (15 percent, in comparison to 1 to 2 percent risk in the general population). If several twin studies are taken together, 72 percent of monozygotic twins are concordant for bipolar disease, compared with 14 percent of same-sex dizygotic twins; comparative figures for unipolar disease are 40 percent and 11 percent, respectively (see Goodwin and Guze). All of these findings indicate a strong genetic factor. The genes for bipolar disease remain to be discovered, and current thinking holds that several are likely to be involved. One indication that specific genes may alter the susceptibility to depression has been presented by Ogilvie and colleagues; they and others have found allelic variations in the serotonin transporter gene (the main target of the selective serotonin antidepressants) that were associated with a sevenfold increased risk of major depression. Not all studies agree on these points. This result has been reinforced by Caspi and colleagues who reported that a variant in the serotonin transporter correlates with an increase in depression in response to stress. Other hypotheses have postulated various susceptibility loci but again, a single gene locus seems unlikely (see Sanders et al).
Several lines of study, including those employing functional imaging, indicate that a few regions of the brain are implicated in the pathogenesis of the complex symptomatology of depression (Drevets). Hypometabolism in the left frontal cortex is among the most consistent findings. Also prominent in many studies are metabolic changes in the cingulate and orbitofrontal cortices, related parts of the medial limbic system, and the hippocampus. As with all functional imaging studies, it is difficult to know if the observed changes are the cause or simply the representation of activity that corresponds to the depressive state.