Substance P serum levels are increased in major depression: preliminary results
Introduction
Substance P (SP) belongs to the neurokinin (tachykinin) peptides and is abundantly expressed in peripheral and central nervous tissues. The findings regarding an anatomical and functional colocalization of SP with central serotonergic and noradrenergic systems Sergeyev et al 1999, Stout et al 2001, which are both cornerstones in the hypotheses of depression (Leonard 2000), have provided an important link between this neuropeptide and the etiology of depression. Also, data from animal studies support the implication of SP, as they have shown a decrease in SP content in several brain regions as a common effect of therapy with various antidepressants (Shirayama et al 1996). On the other hand, sustained blockade of neurokinin-1 (NK1) receptors with selective antagonists was shown to enhance serotonergic transmission (Haddjeri and Blier 2001).
An interaction between SP and the serotonergic system is also discussed in chronic pain syndromes (Crofford et al 1996). A decrease in urinary 5-hydroxyindole acetic acid concentration, together with elevated SP levels in cerebrospinal fluid (CSF), was found in fibromyalgia Kang et al 1998, Schwarz et al 1999 but not in patients with chronic fatigue syndrome (Evengard et al 1998). These clinical results underline the interaction of both systems in fibromyalgia, a syndrome whose pathophysiological mechanisms are often related to depression (Ackenheil 1998). Although similar experimental data are missing for major depression, a clinical study demonstrated that the NK1 receptor antagonist MK-869 exhibited antidepressant and anxiolytic activity comparable to one of the selective serotonin reuptake inhibitors (SSRIs) (Kramer et al 1998). As MK-869 has little or no affinity for the monoamine transporters or the monoamine oxidase, the antidepressant effect may be attributed to its action on the NK1 receptors (Stout et al 2001); however, the efficacy of NK1 receptor antagonists in alleviating depression could not easily be replicated (Kramer et al 2000). Further, as the data of SP measurement in CSF of patients and control subjects are equivocal Almay et al 1988, Berrettini et al 1985, and postmortem investigations about the NK1 receptor densities or messenger ribonucleic acid expression are rare and not supportive of an overall change (Burnet and Harrison 2000), the role of SP and NK1 receptors in the pathophysiology of depression is suggestive but not conclusive (Stout et al 2001).
With respect to the limited data available, we have measured substance P levels in serum of patients with major depression and healthy control subjects to investigate possible differences of this neuropeptide between both groups. We further evaluated the intra-individual stability and correlated the data to depressive symptoms before treatment as well as to the response to antidepressant drugs that primarily affect the serotonergic and adrenergic system.
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Subjects
Twenty-three patients with depressive syndromes (7 male, 16 female; aged 32–76 years; mean ± SD: 51.5 ± 11.54 years) were enrolled in the study (detailed characteristics in Table 1). All patients were diagnosed as having major depression according to DSM-IV criteria using the Structured Clinical Interview for DSM-IV diagnoses (SCID-IV; Spitzer et al 1995). The clinical interviews were carried out by psychiatrists trained for application of SCID-IV for a minimum of 5 years. Studies assessing
Results
In healthy control subjects, the SP serum level was in the range of 132–458 pg/mL (mean ± SD 216.87 ± 81.9; Figure 1). To evaluate the stability of this parameter over time, we re-investigated 19 of the control subjects after a 4-week interval, and our data show that SP in serum is relatively constant and without significant alterations between the two measurements (SP after 4 weeks: 201.3 ± 82.4 pg/mL; Wilcoxon test: Z = −.065, p = .948; Figure 2).
In contrast, the SP data in 23 drug-free,
Discussion
In the present investigation, we have measured the substance P serum concentrations in patients with major depression and in healthy control subjects. Despite considerable overlap between the individual data, the mean SP level was significantly elevated in patients. Substance P serum levels remained relatively constant over a period of 4 weeks in control subjects and also in about 25% of the patients after treatment; however, in 37% of the patients, we observed a decrease (15%–50%) in SP, which
Acknowledgements
Financial support was received from Merck International, Inc.
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