There is a growing evidence that neuropeptides may be involved in the pathophysiology of suicidal behavior. A critical review of the literature was conducted to investigate the association between neuropeptides and suicidal behavior. Only articles from peer-reviewed journals were selected for the inclusion in the present review. Twenty-six articles were assessed for eligibility but only 22 studies were included. Most studies have documented an association between suicidality and some neuropeptides such as corticotropin-releasing factor (CRF), VGF, cholecystokinin, substance P, and neuropeptide Y (NPY), which have been demonstrated to act as key neuromodulators of emotional processing. Significant differences in neuropeptides levels have been found in those who have attempted or completed suicide compared with healthy controls or those dying from other causes. Despite cross-sectional associations between neuropeptides levels and suicidal behavior, causality may not be inferred. The implications of the mentioned studies were discussed in this review paper.
Suicide represents one of the leading causes of premature death in the general population. Higher suicide rates have generally been reported in men compared to women in almost all countries, with elderly men at especially high risk for completed suicide [
Major depressive disorder (MDD) is a chronic and invalidating disease associated with significant functional impairment and occupational disability. Individuals with MDD are at increased risk for suicidal behavior [
Despite the recent advancements in the understanding of suicide, our current knowledge concerning the neurobiology of this complex phenomenon is still limited.
Peptide hormones might play a critical role in normal as well as pathological functions of the central nervous system [
Neuropeptides may modulate a more prolonged transmission than typical neurotransmitters showing relevant neurotrophic effects [
To what extent neuropeptide abnormalities may be considered reliable predictors of suicidal behavior is, however, a matter of debate. Considering this background, we aimed to critically review the current literature about the role of neuropeptides in suicidal behavior.
A detailed search strategy summarized in Figure
Flowchart of the search and selection process identification.
Studies were included according to the following criteria: (a) being an original paper in a peer-reviewed journal and (b) have analyzed the possible involvement of neuropeptides in suicidal behavior. Figure
To achieve a high standard of reporting, we have adopted Preferred Reporting Items for Systematic Reviews and Meta-Analyses, (PRISMA) guidelines [
The recorded variables for each article about neuropeptides and suicide were sample characteristics, study design, type of neuropeptide which has been investigated, main findings, limitations, and conclusions (Table
The combined search strategies yielded a total of 185 articles of which, after a complete analysis, 26 full-text articles were screened and considered for the inclusion in the current review. 159 studies were excluded because they were considered not relevant to the main topic. Specifically, we excluded articles not published in peer reviewed journals and not in English language, articles without abstracts, abstracts that did not explicitly mention the link between neuropeptides and suicide, articles with a publication date before 1985, and those with unclear data regarding materials and methods and number of patients analyzed. As mentioned, we assessed 26 articles for eligibility but 4 full-text articles were excluded due to low relevance to the main theme leaving 22 studies that fulfilled our inclusion criteria.
CRF, oxytocin, and AVP have been hypothesized to play a crucial role in the pathogenesis of major affective disorders and presumably suicidal behavior.
Clinical and basic research supports the notion that these neuropeptides appear crucial in modulating behavior. During the past decade, drug discovery efforts using neuropeptide receptor ligands have focused on a limited number of neuropeptides, such as CRF, oxytocin, and AVP although many other neuropeptide systems have been identified. Table
Neuropeptides that may be relevant in major affective disorders and suicidal behavior.
Corticotropin-releasing |
CRF is a 41-amino-acid neuropeptide that binds the G-protein-coupled receptors CRF1 and CRF2. The association between CRF/CRF1 system and stress-related disorders is well known [ |
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Arginine |
AVP is a nine-amino-acid neuropeptide released by the magnocellular terminals into the posterior pituitary mediating the resorption of water in the kidney. AVP interacts with CRF in the parvocellular neurons with the final aim to modulate HPA-axis activity. AVP transmission is also involved in different functions such as learning and memory, aggression, and sociality [ |
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Oxytocin | Oxytocin is a nonapeptide binding to a single G-protein coupled receptor and mainly implicated in behaviors such as childbirth, lactation and sexual behaviors, social memory, and cognition. Oxytocin is synthesized in the paraventricular and supraoptic nuclei of the hypothalamus, transported to the posterior pituitary and released to amygdala, hypothalamus, hippocampus, and nucleus accumbens. According to animal studies, the infusion of oxytocin stimulates maternal behavior and the administration of antagonists inhibits this behavior [ |
Most relevant studies about the association between neuropeptides and suicide.
Author(s), year | Sample characteristics | Study design and psychometric instruments | Type of neuropeptide which has been investigated | Main findings | Limitations | Conclusions |
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Lindqvist |
124 patients who attempted suicide (63 men, 61 women; mean age |
Patients were evaluated with the Montgomery-Asberg Depression Rating Scale (MADRS), the SIS, and the Suicide Assessment Scale (SUAS). Suicide attempts were divided into violent and nonviolent acts. Principal component analysis of CSF biomarkers were carried out. | Lumbar punctures were performed and samples were stored in aliquots and immediately frozen in −80°C. The following substances were quantified in CSF: eotaxin, eotaxin-3, interferon-gamma-inducible protein-10, interleukin-(IL-) 1 |
Factor 4 characterized by positive loadings of monoamine metabolites 5-HIAA and HVA, the proinflammatory cytokine IL-6, and negative loading on the HPA-axis-associated neuropeptide orexin was associated with violent suicide method, risk for suicide completion, and less impulsivity. | The study did not include a control group. A small subset of the suicide attempters had somatic diagnoses. Whether storage time might have influenced the biomarkers is unknown. | Analyzing clusters of biomarkers in the suicidal patients may improve the clinical assessment of future suicide risk. |
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Stanley |
29 psychiatric patients with a history of one or more suicide attempts with a mean of 3.0 attempts (SD = 2.4). | Patients were assessed using the Hamilton Rating Scale for Depression (HRSD), Beck Depression Inventory (BDI), Brief Psychiatric Rating Scale (BPRS), Clinical Global Impressions Scale (CGI), and Buss-Durkee Hostility Inventory. The sample was divided according to the presence or absence of a history of repeated nonsuicidal self-injury (NSSI) | Cerebrospinal fluid samples were collected via lumbar puncture, and CSF |
Patients in the NSSI group had lower CSF |
Plasma neuropeptide levels may not accurately reflect central levels. Whether results are due in part to the stress response of individuals with NSSI is unknown. | Patients with NSSI have abnormalities in the brain opioid system suggesting the possibility of disordered pain or reward circuitry. |
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Brundin |
4 MDD males and 6 MDD females of |
Patients were evaluated using the SUAS and Comprehensive Psychopathological Rating Scale (CPRS) at baseline, after 6 and 12 months. | Lumbar punctures were performed and samples stored in −80°C. CSF-orexin was analyzed. | CSF-orexin increased significantly between the suicide attempt and the first follow-up, from |
The small number of subjects limits the generalization of findings. Also, the number of patients in the group receiving antidepressive medications was too small for any conclusions to be drawn concerning its effect on CSF-orexin. | CSF-orexin increased significantly during the first year after a suicide attempt and was associated with an improvement (reduction) of the SUAS scores. |
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Pitchot |
28 MDD (19 men and 9 women) inpatients were divided into 13 suicide attempters and 15 nonattempters | No psychometric instruments were used. | Neurophysin blood level which is considered a better method to investigate neuropituitary function was used. Basal plasma levels of AVP neurophysins extracted at 8:00 am and postdexamethasone suppression test (DST) cortisol levels were measured. | There was no correlation between HRSD scores and AVP-neurophysins levels or post-DST cortisol concentrations. Any significant correlation between AVP-neurophysins and post-DST cortisol levels was observed. AVP-neurophysins did not differ between DST suppressors and nonsuppressors. | AVP in plasma reflects neuropituitary AVP release and not AVP activity in the magnocellular portion of the paraventricular nucleus. Also, the study was limited by the weak statistical power. | Results fail to support a possible role of AVP-neurophysins in the control of suicidal behavior. |
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Brundin |
66 patients (with a mean age of |
Patients were evaluated using the CPRS. | Lumbar puncture performed in the morning between 08.00 and 09.00 am after a night of fasting and bed rest and CSF orexin-A levels were measured. | The orexin level was significantly lower in the group of patients with MDD compared to patients with adjustment disorder and dysthymia. Orexin correlated significantly with CSF-levels of somatostatin, delta sleep inducing peptide-like immunoreactivity (DSIP-LI), and CRF. | The study lacks a group of healthy controls. The range |
Orexin neurotransmission |
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Brundin |
101 suicide attempters (51 male and 50 female with a mean age of |
Patients were evaluated using the CPRS. | Lumbar puncture was performed to measure CSF orexin-A. | Significant negative correlations between lassitude and CSF-orexin levels, slowness of movement and CSF-orexin levels and rating of global illness and CSF-orexin levels. | It cannot be ruled out that some other symptoms not assessed in this study may be associated with low CSF-orexin levels. | Low orexin levels were |
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Austin |
11 subjects who died by suicide and having a diagnosis of depression were matched with control subjects. | No psychometric instruments were used. | Postmortem study aimed to evaluate corticotropin-releasing hormone (CRH) levels. | The mean level of CRH-IR in depressed subjects was significantly increased by 30% in the LC, by 45% in the caudal nucleus of the DR, and by 39% in the median raphe relative to controls. The mean level of CRH-IR was not significantly different in the medial parabrachial nucleus and dorsal tegmental nucleus of depressed subjects than controls. A significant positive correlation was found between the magnitude of the increase in CRH-IR levels in the LC and the age at onset of depression. | The study was conducted only in male subjects. The small sample size limits the generalization of findings. | CRH-IR levels were increased in the LC, caudal nucleus of the DR, and median raphe of depressed suicide men compared to controls. CRH neurotransmission is increased in the extrahypothalamic brain regions of depressed subjects. |
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Merali |
Brain samples were obtained from suicides (24 men of 48. |
No psychometric instruments were used. | Brains were obtained 1–6 hours postmortem to measure CRH, AVP, gastrin-releasing peptide (GRP), and neuromedin B (NMB) levels. | Levels of CRH-ir among suicides were increased in the LC, frontopolar, dorsolateral prefrontal, and ventromedial prefrontal cortices but were reduced at the dorsovagal complex. The concentration of AVP-ir was increased at the paraventricular hypothalamic nucleus, LC, and dorsolateral prefrontal cortex and reduced at the dorsovagal complex (DVC). | The considered number of suicides and controls for each brain region was relatively small (there was insufficient power to determine the contribution of gender to the observed peptide differences between suicides and controls). Whether age differences between suicides and controls may account for the observed outcomes is unknown. | Suicide was associated with site-specific alterations in the endogenous levels of CRH, AVP, GRP, and NMB. However, the exact clinical significance of these peptidergic changes in the suicide brain is unclear. |
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Brunner |
19 inpatient suicide attempters (12 female, 7 male) aged |
Depressive symptoms were assessed using HDRS21. |
Lumbar puncture was performed to measure CSF and plasma AVP, CSF, and plasma HVA and plasma N+ and K+. | There were no differences between all 19 depressed subjects and 9 controls with respect to all biochemical parameters measured in CSF plasma. Suicide attempters did not differ from nonattempters. In depressed patients, plasma AVP correlated positively with cortisol. There was no relationship between CSF AVP and monoamine metabolites in CSF. | The small sample size and the heterogeneous diagnoses in the patient population did not allow to rule out a possible pathogenic role of central AVP in suicidal behavior. | No differences in the CSF AVP concentrations between depressed suicide attempters, depressed nonsuicidal patients, and neurological control subjects were reported. |
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Caberlotto and Hurd, 2001 [ |
44 subjects died by suicide with a mean age of 44.1 (6 females and 9 males with MDD, 6 females and 9 males with bipolar disorder, and 5 subjects with other diagnoses) compared to 15 controls (9 males, 6 females) with a mean age of 48.1 years. | No psychometric instruments were used. | Postmortem study aiming to measure Y1 and Y2 receptor mRNA expression levels. | No significant alterations in Y1 or Y2 mRNA expression levels were observed between the groups. The Y2 mRNA expression was elevated in layer IV in subjects with suicide as a cause of death. For the Y1 mRNA expression, there was a negative correlation with increasing subject age in the prefrontal cortex. | Information regarding detailed toxicology and the history of other antipsychotics or antidepressant medications was not available. Several post-mortem parameters may affect the stability of mRNAs and proteins in the human brain. The Y2 mRNA expression was significantly influenced by post-mortem delay. | There are indices of an impairment of the prefrontal cortical NPY receptor mRNA expression in suicide, but this might not relate to the pathophysiology of mood disorders. |
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Inder |
45 MDD patients (27 females and 18 males) aged |
Depressive symptoms were assessed using HDRS17. | Levels of cortisol, ACTH, AVP, and CRH were measured. | There was a significant correlation between ACTH and cortisol, AVP and ACTH, and AVP and cortisol. No significant correlation was observed between plasma CRH and either ACTH or cortisol. There was no relationship between severity of depression as measured on HDRS score and any of the hormone parameters measured. Also, there was no difference in mean cortisol between depressed subjects and controls. Plasma AVP was significantly higher in patients who had attempted suicide. | Although plasma AVP levels were higher in those subjects who had attempted suicide compared to those who did not, differences in ACTH and cortisol levels were not significant. The sample is too small to generalize findings. | There is a significant positive correlation between plasma AVP, ACTH, and cortisol levels in depressed subjects. Also, plasma AVP levels are increased in those subjects who had attempted suicide. |
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Olsson |
13 patients who attempted suicide diagnosed with MDD according to the DSM-III-R criteria. | Patients were assessed using |
Lumbar punctures were performed to examine CSF NPY and SP levels. | Antidepressant treatment seemed to affect the levels of CSF NPY and SP, which decreased significantly between the second and last lumbar puncture. At pretreatment, BSA scores were significantly and negatively correlated with CSF SP and tended to be negatively correlated with CSF NPY. There were also significant positive correlations between CSF NPY and SP in the whole group, possibly reflecting an interrelationship between these neuropeptides. | The small number of patients might have influenced the results. Also, patients were included because of an attempted suicide and not because of a specific diagnosis. The drugs that some of the patients ingested in order to intoxicate themselves may be another confounding factor. | Long-term antidepressant treatment had no specific effect on SP in patients who attempted suicide. It is possible that NPY was affected by long-term antidepressant treatment. |
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Westrin |
16 patients (11 patients with previous suicide attempts). 4 patients had MDD, 5 dysthymia, and 7 other diagnoses. | Drug-free patients were evaluated with the SUAS and MADRS at baseline and after a median of 7 (5 to 9) months. | Lumbar punctures were performed to measure CSF-CRH and CSF somatostatin alterations. | At follow-up, MADRS and SUAS scores were significantly decreased ( |
The substances ingested might have caused the initially low CRH and somatostatin levels. The study did not show whether somatostatin changes are specifically related to either suicidality or depression. | CSF somatostatin but not CSF-CRH seems to increase with clinical improvement in suicidal patients, independently of psychiatric diagnoses. |
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Westrin |
36 suicide attempters (mean age |
Patients were evaluated using MADRS and SUAS. | Serum and plasma cortisol, CRH, NPY, and beta-endorphin (beta-END), were measured. | When compared with healthy controls, cortisol was high ( |
Whether the observed alterations depend on the underlying depression or stress associated with a suicide attempt is unknown. The small sample size did not allow the generalization of findings. | There may be alterations in CRH and NPY plasma levels in patients with a mood disorder who were recent suicide attempters. |
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Westrin |
34 patients (mean age |
Patients were evaluated using MADRS and SUAS. | DSIP-LI levels were measured. | Significantly elevated DSIP-LI levels in MDD patients and a significant correlation between predexamethasone cortisol and predexamethasone DSIP-LI levels in healthy controls were found. Postdexamethasone DSIP-LI levels increased in subjects with low predexamethasone DSIP-LI levels whereas they decreased in subjects with high predexamethasone DSIP-LI levels. | A nonsuicidal control group was not included. The small sample size did not allow to generalize findings. | Suicidal MDD patients and patients with previous suicide attempts had increased plasma DSIP levels. |
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Westrin |
A total of 38 suicide attempters (mean age of |
Patients were assessed using Karolinska Scales of Personality, the Eysenck Personality Questionnaire (EPQ), Impulsiveness-Venturesomeness-Empathy (IVE) Inventory (EPQI) and the Marke-Nyman Temperament (MNT). | Serum and plasma samples for cortisol, DSIP-LI, CRH-LI, and NPY-LI were measured. | NPY correlated positively with psychasthenia, irritability, and stability and negatively with validity in patients, but negatively with muscular tension, psychasthenia, verbal aggression, and irritability in controls. DSIP correlated positively with impulsiveness (EPQI) in controls. CRH correlated negatively with the temperament dimension of lie in controls. Cortisol correlated positively with validity, extraversion and verbal aggression and negatively with inhibition of aggression in controls. | Nonsuicidal patients were not included in the analysis. The small sample size did not allow to generalize findings. | Different correlational patterns in patients and controls are probably due to plasma peptides or cortisol as well as some temperament dimensions being state rather than trait related. |
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Roy, 1993 [ |
Depressed patients who had attempted and repeated suicide after the 5-year follow-up period. | A 5-year follow-up was performed | CSF concentrations of NPY, somatostatin, diazepam-binding inhibitor, gamma-aminobutyric acid (GABA), or CRH were analyzed. | There were no significant differences between depressed patients who did or did not repeat suicide during the follow-up or who had never attempted for CSF concentrations of the NPY, somatostatin, diazepam-binding inhibitor, GABA, or CRH. | A non-suicidal control group was not included. | NPY, somatostatin, diazepam-binding inhibitor, GABA, or CRH are not major determinants of suicidal behavior or its repetition in depression |
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Widdowson et al., 1992 [ |
Suicide victims and individuals dying a sudden natural or accidental death (controls). | No psychometric instruments were used. | Post-mortem study in which NPY-concentrations in frontal (BA 10) and temporal cortex (BA 22), caudate nucleus, and cerebellum were analyzed. | NPY levels were significantly lower in postmortem frontal cortex (−14%) and caudate nucleus (−27%) from suicide victims compared with age-matched controls. Suicides with a history of depression displayed more robust reductions in NPY immunoreactivity in frontal cortex and caudate nucleus, as did 4 subjects who died from natural causes and were also described as having a possible history of depression. | Other post-mortem parameters that were not investigated may have affected NPY concentrations in the human brain. Subjects were not evaluated with psychometric instruments. | An NPY deficit in the brain leading to region-specific reductions in peptide concentrations in subjects who have a history of depression was found. |
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Ordway |
Suicide victims having MDD established by psychiatric autopsy compared to controls (who had died by natural or accidental death). | No psychometric instruments were used. | Post-mortem study in which NPY concentrations in frontal cortex were analyzed. | No significant differences in NPY concentrations were observed between control subjects and suicide victims with MDD or alcohol dependence. | Several subjects with MDD had a comorbid diagnosis of alcoholism. | The possible role of NPY in MDD was not confirmed. |
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Träskman-Bendz |
44 suicide attempters diagnosed with MDD. | Patients were evaluated using MADRS. | Lumbar punctures were performed to measure the following HPA-axis related peptides: CRH, somatostatin, DSIP, NPY, beta-END, and AVP; serotonin metabolite 5-HIAA in CSF and postdexamethasone plasma cortisol were also measured. | Strong correlations between CRH and the peptides somatostatin and beta-END, with the latter also correlated positively with somatostatin. There were no gender differences. Patients with MDD had significantly lower somatostatin, CRH, and DSIP than other patients. Both somatostatin and beta-END correlated negatively with postdexamethasone plasma cortisol in all patients. No significant relationships between neuropeptides and CSF 5-HIAA were found. Patients who had made previous suicide attempts had significantly lower CRH than those who had not. | The study was cross-sectional in nature. Other neuropeptides which were not investigated may affect the HPA regulation. | There was no indication of specific neuropeptide patterns in those MDD patients who later completed suicide. |
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Scarone |
7 suicides and 7 dying a sudden natural death (controls). | No psychometric instruments were used. | Post-mortem study in which beta-endorphin levels were analyzed. | Reduced beta-endorphin levels in the left temporal cortex, left frontal cortex, and left caudate nucleus of suicides compared to controls were found. An asymmetrical concentration of beta-endorphin in suicides (left less than right) in frontal cortex and caudate nucleus was also found. | The small sample size did not allow to generalize findings. | Suicidal behaviour might be related to the lateralized mechanisms of mood control. |
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Maes |
17 suicidal and 17 non-suicidal female MDD patients matched for age and severity of illness. Subjects were divided in to those with suicidal ideation and those without. | No psychometric instruments were used. | Thyroid-stimulating hormone (TSH), free thyroxin (FT4), pre- and postdexamethasone cortisol, ACTH levels, the circulating concentrations of total L-tryptophan (L-TRP), and the ratio between L-TRP and competing amino acids (CAA) were measured | No significant differences in any of the examined biological data between patients with suicidal ideation and those without. | The study was cross-sectional in nature. Subjects were not evaluated with psychometric instruments. | The possible role of TSH, FT4, ACTH levels, and L-TRP was not confirmed in suicidal patients. |
Galanin (GAL) is a 30-amino-acid peptide that binds GAL receptor1 (R1), GALR2, and GALR3 found along the HPA axis and involved in several human functions such as food and alcohol intake, metabolism, osmoregulation, seizure threshold, and reproduction. Depression-like behaviors seem to be induced by the activation of GALR1 and attenuated depression-like behaviors derived by the activation of GALR3 [
SP that binds three different g-protein-coupled tachykinin receptors—NK1, NK2, and NK3, has been associated with nociception, respiration, cardiovascular and thermoregulation, gut motility, emetic response, and stress-related disorders [
NPY is a 36-amino-acid which is involved in circadian rhythms, neurogenesis and neuroprotection, nociception, feeding behavior and energy regulation, neuronal excitability, emotion and cognition, stress response, and resilience. NPY action is associated with several neurotransmitters such as GABA, serotonin, norepinephrine, and other catecholamines [
The enhanced NPY transmission might be stimulated to control stress response through the modulation of CRF and noradrenergic tone. In fact, the reduced NPY transmission may be related to increased CRF and noradrenergic transmission determining anxiety and depression behaviors [
CCK is a 33-amino-acid peptide that has been found to be implicated in gastric emptying, gallbladder contraction, pancreatic enzyme release, and suppression of appetite. CCK levels were observed in the cortex, hippocampus, amygdala, nucleus accumbens, striatum, and substantia nigra [
The interaction of CCK with CCKR2 has been reported to inhibit dopamine release blocking dopamine-mediated behaviors into the anterior nucleus accumbens whereas the binding with CCKR1 into the posterior nucleus accumbens is associated with opposite effects [
The complete sequence of dynorphin A (Dyn-A) (17amino acids) was identified by Goldstein et al. [
Orexins or hypocretins and their receptors have been discovered in 1998 as predominantly expressed in the lateral hypothalamus [
Hypocretin fibers such as the central nucleus of the amygdala (CeA), bed nucleus of the stria terminalis (BNST), LC, and paraventricular nucleus of the hypothalamus (PVN) might have a specific role in the regulationof stress responses [
Neuropeptides may play a key role in the stress response as well as in the regulation of several human behaviors. Table
Important insight into the role of neuropeptides in the pathogenesis of MDD and suicidal behavior has been given. Orexin alterations have been investigated in several subgroups of patients. In a factor analysis of CSF biomarkers in suicide attempters, a negative loading on orexin, along with positive loading on proinflammatory cytokine interleukin-6 and monoamine metabolites 5-HIAA and HVA was associated with violent suicide method and risk for future suicide completion [
Furthermore, Inder et al. [
Patients with NSSI were also investigated in order to find abnormalities in neuropeptides. Stanley et al. [
The excessive CRH secretion and neurotransmission which is involved in the pathophysiology of depressive disorders has been suggested to extend beyond the hypothalamus and to involve several extrahypothalamic brain regions. Austin et al. [
In addition, Träskman-Bendz et al. [
Westrin et al. [
Whether psychoactive treatments affect neuropeptides levels is a matter of debate. Olsson et al. [
Also, post-mortem studies have been conducted in order to analyze the possible role of neuropeptides in suicidal behavior. Merali et al. [
Moreover, Widdowson et al. [
Negative findings have also been reported. Pitchot et al. [
In a 5-year follow-up study, Roy [
The present review supports a role of neuropeptides in the pathophysiology of suicidal behavior. Based on the included studies, there may be associations between neuropeptides and suicidal behavior but this does not imply the existence of a causal link. Most studies (thirtheen) [
One relevant limitation of the selected studies is related to the variable neuropeptide concentrations (e.g., some studies reporting increases and others reporting reductions or no significant changes) in those who attempted suicide or died by suicide compared with healthy controls or those dying a sudden natural or accidental death, respectively. These findings reflected the significant heterogeneity in terms of psychopathology which is commonly observed in those with suicidal behavior together with the variability in the antidepressant response which may be found in these different subgroups of patients. Specific stressors may induce specific neuropeptide responses: SP may be evoked by structural damage, oxytocin release by social threats, melanin-concentrating hormone (MCH) by abnormal energy homeostasis, and AVP changes by blood volume changes, respectively. Neuropeptides such as CRF, VGF, CCK, SP, and NPY have been demonstrated to act as key neuromodulators of emotional processing [
Neuropeptides may be considered as crucial molecules in the interaction between genes and environment as well as fundamental mediators of the stress response able to in turn affect gene regulation in order to respond to the different environmental stimuli. What is the main mechanism underlying neuropeptides alterations in subjects with suicidal behavior? Evidence suggests that modulation of monoaminergic transmission may represent the main mechanism by which the neuropeptide galanin was implicated in stress-related disorders [
The role of NPY and its receptors in affective disorders and stress-related conditions has been investigated for over two decades but still remains rather controversial. According to behavioral findings on NPY, Y1, and Y2 receptors in animal models, evidence suggested an important role of NPY in emotional responses and stress- or depression-related disorders [
Pitchot and colleagues [
Finally, based on Maes et al. investigation [
Many of the mentioned studies should be considered in the light of the following shortcomings. Many studies were not completely informative over time and lacked adequate long-term follow-up periods. The naturalistic designs may not completely control for the effect of confounding factors such as the duration of treatment and disease and the diagnostic subtypes. Also, samples were often too small or included mixed, heterogeneous patients and usually did not allow to generalize findings. Patients with suicidal behavior who were included in these studies may be affected by different psychiatric disorders; the methods of suicide attempts were not controlled in all studies. Differences may exist between participants and those that did not accept to participate in the studies. Furthermore, some of these studies may lack a control group or, alternatively, controls were not matched for age and other clinically relevant information. In addition, psychometric instruments evaluating suicide risk were not used in all studies.
Moreover, many of the observed abnormalities in neuropeptides concentrations were found in subjects with suicidal behavior who were also depressed. It is possible that the association between neuropeptides and suicidality may be mediated by the existence of psychiatric conditions such as major affective disorders. Generally, the variability in the concentrations of neuropeptide markers is too great to draw any definitive conclusion in those who were depressed and also displayed suicidality.
In light of recent advances in understanding the regulation of genes encoding neuropeptides, neuropeptide receptors have emerged as attractive targets for the treatment of many psychiatric disorders. To date, many molecules have been synthesized but none has been introduced into the market due to the failure of most clinical trials aimed to show their efficacy. Griebel and Holsboer [
Biomarkers and genetic tests are suggested to identify clinical conditions that may be related to a specific neuropeptidergic mechanism. The specificity of the mechanism of action of the different neuropeptides should also be adequately considered. An important research question that needs to be addressed in future studies is how and when personalizing treatments using drugs targeting neuropeptide receptors are possible. This implies the knowledge of whether subjects could preferably respond to a medication or another, which may be the right combination of medications, and what is the real benefit for some subgroups of patients.
The possibility to select medications targeting neuropeptide receptors according to findings derived from animal studies should be carefully considered using models evaluating different aspects of the disorders.
A detailed characterization of patients based on objectifiable measures, genetic tests, and reliable biomarkers is undoubtedly requested.
According to most of the studies included in the present review, neuropeptides may play a key role in the pathophysiology of suicidal behavior. In particular, one mechanism by which neuropeptide alterations may promote suicidal symptoms is via changes in monoaminergic systems rendering neuropeptides as novel, intriguing mediators of stress-related and affective conditions as well as suicidality.
However, despite the recent advances in this research field, it is unlikely that neuropeptides represent definitive and reliable markers of suicidality. Further additional studies will elucidate the pathophysiological mechanisms of the different neuropeptides pathways underlying suicidal behavior.