An intriguing observation, and one that does not entirely accord with the above, has been made by Bejjani and colleagues in the course of deep brain stimulation for the treatment of Parkinson disease. One of their patients displayed transient but dramatic manifestations of depression only when high-frequency stimulation was delivered to the left substantia nigra. Positron emission tomography imaging during stimulation showed activation in the left orbitofrontal cortex and, less consistently, in the left amygdala, globus pallidus, thalamus, and right parietal lobe. In 2 other cases with no prior psychiatric symptoms, deep brain stimulation of the subthalamic nucleus induced a reversible manic state (Herzog et al; Kulisevsky et al). Fisher noted a hypomanic episode in the early stages of herpes encephalitis, and numerous cases of temporary secondary mania have been reported after stroke and after brain trauma, the latter affecting most often the right temporal lobe. It is likely that the structures implicated in these cases are part of a larger and widely distributed network that is activated during depression.
On the histologic level, several studies have shown a depletion of and changes in the pyramidal neurons of the CA3 region of the hippocampus in both depression and stress, but the meaning of these findings is unclear (Sapolsky). They are referred to later in relation to neurogenesis (the appearance in adults of new neurons) in the temporal lobe and recovery from depression. These ideas regarding neurogenesis, which are still speculative, are discussed in Chap. 28. Interestingly, in a rodent model of depression, neurogenesis was required for the beneficial effects of antidepressants to take place (Santarelli). Based in part on this observation, a relationship has been suggested between depressive illness and the later development of dementia. The reviews of Starkstein (1987, 1991) and Robinson, and that of Belmaker and Agam mentioned earlier, may be consulted for further information on anatomic lesions that cause changes in affect. Evolving work on alterations in the brain connectome in mania have give varied results but focus on decreased activity between various brain hubs that are considered “rich” in connectivity and between the hemispheres (Collin et al) but these are not easily applicable concepts and will probably change as more investigation is performed.
It has been evident for several years that the biogenic monoamines (norepinephrine, serotonin, and dopamine) are in some way involved in the biology of depression. However, most of the neurochemical theories of depression suffer from the weakness that they have been the result of backward reasoning from the effects of antidepressants on various neurotransmitters to the putative mechanisms of the disease. Following the observations that the tricyclic antidepressants and the monoamine oxidase (MAO) inhibitors exerted their effect by increasing norepinephrine and serotonin at central adrenergic receptor sites in the limbic system and hypothalamus and that depression-provoking drugs (such as reserpine) deplete biogenic amines at these sites, it was proposed that naturally occurring depressions might be associated with a deficiency of these substances. Furthermore, depressed patients and their first-degree relatives, as well as healthy individuals, develop a depressed mood after dietary depletion of the monoamine precursor tryptophan, and concentrations of 3-methoxy-4-hydroxyphenylglycol (MHPG), a metabolite of norepinephrine, are reduced in the cerebrospinal fluid during endogenous depression and the levels are elevated in manic states. Some neurochemical imaging studies corroborate these findings and others do not. Along similar lines, 5-hydroxyindoleacetic acid (5-HIAA), a deaminated metabolite of serotonin, is reduced in the cerebrospinal fluid of depressed patients (Carroll et al).