Elsevier

Biological Psychiatry

Volume 53, Issue 6, 15 March 2003, Pages 538-542
Biological Psychiatry

Substance P serum levels are increased in major depression: preliminary results

https://doi.org/10.1016/S0006-3223(02)01544-5Get rights and content

Abstract

Background

Substance P (SP) is thought to have an impact in the pathophysiology of depression and the mechanism of action of antidepressant drugs. The aim of this study was to analyze the serum SP levels in healthy control subjects and in depressed patients before and after antidepressant treatments.

Methods

Twenty-three patients with major depression and 33 control subjects participated in the study. Using an enzyme immunoassay, the SP serum levels were determined in patients at baseline (before treatment) and after 2 and 4 weeks of antidepressant therapy. Determinations of SP in control subjects were carried out twice, at baseline and after 4 weeks.

Results

The mean baseline SP serum concentration was significantly higher in depressed patients as compared with control subjects (p < .001). Repeated measurements in control subjects showed that SP remains relatively constant over a period of 4 weeks. Although in depressed patients there was no overall change in the mean SP levels between baseline and 4 weeks’ treatment, 37% of them exhibited a decrease of SP (15%–50%), which can be correlated to a better drug response than an increase in SP concentration after treatment (p = .001).

Conclusions

Our data show that serum SP levels are increased in a proportion of patients with major depression and might thus indicate a subgroup of the disorder in which neuropeptides have a key position. Future studies are needed to clarify whether the observed SP decrease in treatment responders can be attributed to a specific class of drugs.

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.

Section snippets

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.

References (27)

  • M. Ackenheil

    Genetics and pathophysiology of affective disordersRelationship to fibromyalgia

    Z Rheumatol

    (1998)
  • T. Baghai et al.

    Possible influence of the insertion/deletion polymorphism in the angiotensin I-converting enzyme gene on therapeutic outcome in affective disorders

    Mol Psychiatry

    (2001)
  • Y.K. Kang et al.

    Low urinary 5-hydroxyindole acetic acid in fibromyalgia syndromeEvidence in support of a serotonin-deficiency pathogenesis

    Lyon Mediterranee Medical Medicine du Sud-Est

    (1998)
  • Cited by (109)

    • Exploring the role of neuropeptides in depression and anxiety

      2022, Progress in Neuro-Psychopharmacology and Biological Psychiatry
    • Targeting the renin angiotensin system for the treatment of anxiety and depression

      2020, Pharmacology Biochemistry and Behavior
      Citation Excerpt :

      ACE in the CNS also helps to degrade substance P, which has a pro-depressant effect (Skidgel and Erdos, 1987). In fact, depressed patients show elevated substance P levels in both CNS (Rimon et al., 1984) and peripheral plasma (Bondy et al., 2003). Also, substance P antagonists have antidepressant effects (Kramer et al., 1998).

    • Nucleus Accumbens Tac1-Expressing Neurons Mediate Stress-Induced Anhedonia-like Behavior in Mice

      2020, Cell Reports
      Citation Excerpt :

      SP, dopamine 1 receptors (D1), and dynorphin co-express in the MSNs of the direct pathway (Anderson and Reiner, 1990; Besson et al., 1990). It has been reported that SP and NK1-R are involved in the pathophysiology of major depression (Bondy et al., 2003; Geracioti et al., 2006; Kramer et al., 1998). However, the clinical efficacy of antidepressant treatment using NK1-R antagonists is still debatable (Keller et al., 2006; McLean, 2005).

    View all citing articles on Scopus
    View full text