In the brainstem, the most primitive part of the brain, lie clusters of serotonin neurons. The nerve fiber terminals of the serotonergic neurons extend all throughout the central nervous system from the cerebral cortex to the spinal cord. This neurotransmitter is responsible for controlling fundamental physiological aspects of the body. Included among these aspects are motor activity, cardiovascular activity, respiration, and control of body temperature. Not only does this bioamine control physiological aspects of the body, but it also has an involvement in behaviors like eating, sleeping and aggression (Jacobs, 1994). Not surprisingly, serotonin is implicated in a broad range of serotonin disorders like depression, schizophrenia, and Parkinson's disease (Jacobs, 1994). The purpose of this paper is to examine the link between serotonin and major depression.
Although historically depression has been considered a character condition, evidence has accumulated suggesting the role of a biological substrate, namely serotonin, in subgroups of depressed patients. This accumulated evidence supports the indoleamine hypothesis of depression which suggests that major depression results from a deficiency of available serotonin or inefficient serotonin receptors (Mann et al., 1996). Among the evidence supporting this hypothesis is the effectiveness of selective serotonin reuptake inhibitors (SSRIs) on depression. Serotonin's action in the synapses is terminated by reuptake of the neurotransmitter by the presynaptic cell. SSRIs block the reuptake of serotonin which leads to increased serotonergic action. Fluoxetine, a selective serotonin reuptake inhibitor, has been shown to effectively eliminate the symptoms of depression. In a group of smokers with a history of depression, treatment with fluoxetine ameliorated the symptoms of depression (Dalack et al., 1995). Similarly, high dose fluoxetine treatment (60-80 mg/day) was an effective treatment in patients who were previously resistant to treatment for depression with a lower dose of fluoxetine (20 mg/day)(Fava et al., 1994). These antidepressant effects are reversed when the levels of tryptophan, the serotonin amino acid precursor, are decreased by dietary manipulation (Mann et al., 1996). This reversal of antidepressant effects lends additional evidence to the indoleamine hypotheses.
Another piece of evidence in support of the indoleamine hypothesis is the reduced levels of 5-hydroxyindolacetic (5-HIAA) acid, a serotonin metabolite, in the cerebral spinal fluid of depressed patients. This reduction of 5-HIAA appears to more apparent in depressed patients who have exhibited suicidal behavior. In one study, the 5-HIAA levels were examined in thirty depressed patients with a history of suicidal behavior. Compared to the normal control subjects, the depressed patients had significantly lower 5-HIAA levels in the cerebral spinal fluid (Ricci et al., 1990). Similarly, in another study, twelve normal healthy males with no history of depression were caused to display symptoms of depression. This transformation was accomplished by feeding the subjects a tryptophan free amino acid mixture. This convincing study suggested a correlation between decreased levels of serotonin and depression and support the hypothesis that low serotonin levels predispose an individual to depression.
In addition, genetic studies have provided evidence implicating an abnormality in serotonin function in depression. One such genetic study examined the relationship between polymorphisms of the serotonin transporter gene and the occurrence of depression. The serotonin transporter protein is the primary target of antidepressant drugs and is encoded by a single gene. A polymorphic region containing a variable-number-tandem-repeat (VNTR) element of 17 base pairs exists in the second intron (Olgilvie et al., 1996). Alleles of the gene were identified which contain nine, ten, and twelve copies of the repeat. The presence of the allele with nine copies of the repeat was significantly associated with the risk of depression, and consequently, it may confer susceptibility to unipolar depression (Olgilvie et al., 1996). Variations in the VNTR region in the serotonin transporter protein gene are suggested to play a role in regulating transcription. Conversely, a lower number of repeats may influence the stability of transcription complexes or the concentrations of messenger RNA (Olgilvie et al., 1996). These changes resulting from the variations in the VNTR region may lead to a susceptibility to depression.
The reduction or alteration in function of platelet serotonin-related proteins in depressed patients also suggests the role of a defective serotonin system in depression. One study compared serotonergic function in patients with primary dysthymia and in normal volunteers by measuring serotonin uptake. Dysthymia is morbid anxiety and depression accompanied by obsession. In the dysthymic patients, the maximal rate of transport into platelets was seventy-eight percent lower than in the normal volunteers (Ravindran et al., 1994). This decreased platelet serotonin uptake is suggestive of a deficiency in the serotonergic function. Along the same lines, low numbers of platelet and brain serotonin transporter sites have been identified in drug-free depressed patients (Nemeroff et al., 1994). One hypothesis explaining the reduced number of transporter sites states that this reduction of binding sites results from prior antidepressant treatment. Using imipramine, an inhibitor of serotonin uptake, Nemeroff et al. measured and compared platelet serotonin transporter binding in untreated depressed patients and normal comparison subjects. The study concluded the lower number of serotonin binding sites did not result from prior drug treatment. Similarly, the platelet serotonin transport binding was measured using imipramine and paroxetine, another inhibitor of serotonin uptake. The depressed patients exhibited a lower density of binding sites than the normal comparison subjects confirming the reported low platelet serotonin transporter binding in depressed patients. It was suggested that mRNA expression of the transporter may be abnormal in patient with low platelet serotonin binding sites (Nemeroff et al., 1994).
Hormone responses to indirect serotonin agonists like L-tryptophan also lend evidence to the indoleamine hypothesis. Upon stimulation of the serotonin system, the hormones, prolactin and growth hormone are released. Neuroendocrine responses to intravenous L- tryptophan were examined to compare the serotonergic function in depressed patients and healthy comparison subjects. Prolactin and growth hormones responses to the intravenous L- tryptophan were decreased in depressed patients (Price et al., 1991). This finding supports the evidence that the serotonin function is abnormal in depression.
Motor retardation, cognitive impairment, memory lapses, and apathy are symptoms usually associated with depressions. As mentioned previously, serotonin is thought to play a role in motor activity. More specifically, it was suggested that brain serotonin system controls the facilitation of tonic motor actions and inhibiting sensory-information processing (Jacobs, 1994). Serotonergic neurons functioning abnormally or not facilitating tonic motor activity explains the listless feeling and requirement of maximal energy exertion to accomplish small tasks experienced by depressed patients. Similarly, the memory associated problems may result from abnormal serotonergic activity during sensory information processing (Jacobs, 1994).
Each of previous mentioned approaches indirectly tests the indoleamine hypothesis. A more direct measurement involved investigation of regional brain serotonin responses in the brain of depressed patients. Mann et al. developed a method which enabled the visualization of in vivo brain responses to serotonin release by comparing regional brain glucose metabolism after administration of dl-fenfluramine, a serotonin releasing drug.. Significant increases in glucose metabolism , namely in the left prefrontal and temporoparietal cortex, and decreases in metabolism in the right prefrontal cortex were observed in healthy patients. Depressed patients, however, had no areas of decrease or increase in glucose metabolism (Mann et al., 1996). Hence this study provides direct in vivo evidence of a decreased regional brain response to serotonin release in depressed patients. Additionally, it supports the indoleamine hypothesis of depression.
Over the years, evidence has accumulated indicating that major depression results from a deficiency in serotonin or decreased activity of serotonin receptors. The evidence in support of this theory comes from a range of domains including genetic studies, the effectiveness of selective serotonin reuptake inhibitors, and reduced levels of platelet serotonin. More convincingly, direct evidence has been provided by Mann et al. (1994) to support the correlation between an abnormal serotonergic system and depression.