We have found substantial increase in peptide excretion in severe depression. To our surprise the level was found to be decreased in treated patients. Increase in peptides especially in urine is usually due to peptidase deficiency or inhibition [
13,
14]. The presented data indicate that severely depressed patients show hyper-peptiduria as would be expected if peptidase defects were present. Peptidase deficiencies have been found in depression and melancholic states [
15‐
19]. Because the level and pattern of peptides differ, and differing chain lengths of peptides with the same activities are found, this points to a heterogeneity of genetics. Different families may have a different sets of dysfunctional enzymes probably peptidases or peptidase binding proteins. This may explain the difficulty of pinpointing a specific gene as the genetic disposition in depression. We suggest that we have depression causing genes which may cause formation of different but overlapping peptidases or peptidase regulating proteins, and that the mediators of depression may be peptides regulating the uptake and release of different transmitters. Since antidepressant medication reduced the level of peptides (table
1) this could be due to peptidase induction as has been shown for neuroleptic medication. It remains to be seen if peptide level correlates with the degree of depression. The presence of opioids may explain the psychotic features of our patients because opioids have been shown to cause increased dopamine in the synaptic cleft by inhibiting reuptake [
20] An exogenous supply of peptides may also explain the often seen and peculiar fluctuating course of the disorder with morning worsening and afternoon a relative high or agitation. Increased reuptake of serotonin into platelets may have relevance to the reported changes in serotonin transport into platelets in depression [
21,
22]. Both the tri-cyclic antidepressants and selective serotonin re-uptake inhibitors have the opposite effect on serotonin uptake. We have previously found the tri-peptide but amidated, in autistic patients' urine and this tri-peptide stimulated the serotonin transporter mediated uptake of serotonin in hamster ovarial cells transfected with the human serotonin transporter gene [
23]. That tri-peptide doubled the serotonin content of platelets when injected into pups subcutaneously [
24]. 5 HT 2a receptors are increased in brain tissue and platelets in depression [
25] which would agree with decreased levels in the synaptic cleft due to stimulated uptake. Also the decreased 5HIAA (5-hydroxy indole-acetic acid) in suicidal patients fit an increased uptake [
26]. The tri-peptide sequence has only been found in reelin, which is a matrix proteinase [
27]. That food derived peptides are taken up has been demonstrated [
28,
29] and is increased by peptidase defects [
30]. Depression has been found in cases of coeliac disease [
31,
32] indicating that such a mechanism is not unreasonable. Considerable differences in rates in different cultures may also thus be explainable. Other groups have found increases in some peptides in depression. Thus TRH (pE-H-P-NH2) has been found increased in CSF [
33,
34]; beta-endorphin [
35] and an unspecified opioid fraction 1 measured by receptor binding [
36,
37]. Substance P was also found increased in CSF [
38], and delta sleep factor increased in plasma [
39,
40]. Also plasma arginine vasopressin increase in depression was inversely related to daytime motor activity [
41]. Furthermore post partum psychosis may be mediated by different human caso-morphines [
42] and shows depressive traits. Since peptides in general are excellent peptidase inhibitors [
43] and peptides also have strong tendencies to form complexes [
44,
45] and bind to other molecules and membranes [
46,
47], a rather complex situation with varied results can be envisioned. Bell shaped dose responses are common to many peptides and add to this complicated picture [
12]. The nature of some of these peptides is shared with schizophrenia and may constitute the common features of these disorders [
48]. Possibly relevant to a gut-brain axis in depression is epidemiological data showing very high frequency of depression in irritable bowel syndrome [
49‐
51]. Future work is needed to elucidate if there is a correlation of peptide increase and degree of depression and to look for any correlations between individual peptide peaks and specific symptoms of this disorder.