Monoaminergic Transmitter Systems
Alexander Neumeister and Dennis S. Charney
There is considerable evidence available in the literature supporting the idea that brain monoamine systems play a key role in the pathogenesis of affective disorders, in particular depression. These hypotheses have primarily taken the form of proposing abnormal regulation in serotonin (5-HT) (Coppen, 1967) and the catecholamines norepinephrine (NE) (Bunney and Davis, 1965; Schatzberg and Schildkraut, 1995) and dopamine (DA) (Kapur and Mann, 1992)in depression. Early studies have focused largely on levels of monoamines and their receptors and have stimulated several theories about the pathophysiology of depression, including the monoamine deficiency and receptor sensitivity hypotheses. However, we have to acknowledge today that these hypotheses have not provided us with an ultimate explanation about the role of monoamines in depression. Nor can the pathophysiology of depression be explained simply by dysregulation of 5-HT and/or NE or DA transmission. Recent advances in molecular and cellular neurobiology have offered new insights into mechanisms possibly involved in the pathophysiology of depression, and also into the mechanisms of action of antidepressant treatment modalities (for reviews see Duman et al., 1997; Manji et al., 2001; Sulser, 1989). These studies have shown that chronic antidepressant treatment regulates intracellular signal transduction pathways and the expression of specific target genes.
The purpose of this chapter is to provide a concise review of clinical studies on the role of 5-HT and NE transmission in depression. However, several caveats need to be considered. First, depression is not a homogeneous disorder, and classifying a given patient with depression is a clinical decision and remains a subjective interpretation of a syndrome, even though the decision should be based on established diagnostic criteria such as DSMIV criteria (American Psychiatric Association, 1994). However, identifying homogeneous groups of patients with depression has proven to be a virtually impossible task. This might explain some of the variability of biological findings in depression and the lack of consistent replication of many intriguing findings. Second, almost all patients being studied in clinical studies have been exposed to different pharmacological and non-pharmacological treatments before entering studies. This may confound the results of clinical and preclinical studies. Finally, there is no methodological homogeneity in processing experimental samples and assays. It is remarkable that despite these methodological problems a number of neurochemical findings have been replicated in the past in patients with depression and have provided researchers with insight into the underlying biology of this devastating illness.
Serotoninergic neurons are located in the brainstem where they can project to virtually every part of the central nervous system, often modulating neuronal responses to other neurotransmitters. As a result of this widespread projection pattern, 5-HT is known to be involved in the regulation of a wide variety of functions, including mood, anxiety, aggression, sleep, arousal, appetite and sexual function. However, it has to be acknowledged that the precise details of the mechanisms involved are not fully understood. Interest into the potential role of 5-HT in the pathophysiology of psychiatric disorders was spurred by the observation that hallucinogens such as lysergic acid diethylamide and psilocybin inhibit the peripheral actions of 5-HT. This led to the hypothesis that brain serotonergic function might be altered in patients with psychiatric disorders (Gaddum and Hameed, 1954; Wooley and Shaw, 1954). Further evidence for the importance of serotonergic mechanisms in depression was inferred by the observation that imipramine improved mood and boosted psychomotor activity (Kuhn, 1958). This initial observation of the antidepressant properties of imipramine led to more intensive testing in clinical trials of this compound and later the other tricyclic antidepressants and monoamine oxidase inhibitors for the treatment of depression. The results from these clinical trials, indicating that the action of antidepressant drugs involves enhancement of brain serotonergic activity, and further evidence for dysfunction at multiple levels in the serotonergic system of depressed patients culminated in the 'serotonin hypothesis' of depression (Maes and Meltzer, 1995). Whether this serotonergic dysfunction is the primary cause of depression or is a necessary risk factor remains unclear and is the subject of intensive research.
One factor that has to be considered when evaluating the potential role of 5-HT in depression is the seasonal variation in central and peripheral 5-HT function in humans. There is considerable evidence in the literature suggesting a seasonal variation in several phenomena, such as mood, feeding behaviour and suicide, and that these phenomena may be related to changes in central and peripheral 5-HT function (Maes et al., 1995). In healthy subjects and non-psychiatric patients several studies have described seasonal variations in central and peripheral 5-HT function. Studies of humans distinguish whether measures are static (e.g. biochemical levels in body fluids or blood elements) or dynamic (e.g. neuroendocrine responses to pharmacologic challenges).
Several lines of evidence based on static measures support the hypothesis of seasonal fluctuations of 5-HT function in humans: (1) hypothalamic 5-HT concentrations in human post-mortem brain specimens are decreased in winter after values peak in autumn (Carlsson et al., 1980), (2) levels of plasma tryptophan, the precursor of 5-HT, show a bimodal seasonal pattern (Maes et al., 1995), (3) platelet 5-HT uptake and 3[H]-imipramine binding show a seasonal pattern, albeit with some differences in seasonal peaks and troughs (Arora and Meltzer, 1988; DeMet et al., 1989; Tang