Table 2: Most relevant studies about the association between neuropeptides and suicide.

Author(s), yearSample characteristicsStudy design and psychometric instruments Type of neuropeptide which has been investigatedMain findingsLimitationsConclusions

Lindqvist
et al., 2011 [83]
124 patients who attempted suicide (63 men, 61 women; mean age ), of which 35 with MDD, 13 with depression not otherwise specified (NOS), 28 with adjustment disorder, 17 with dysthymia, and 31 with other DSM-IV diagnoses.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-) 1β, IL-6, IL-8, macrophage-derived chemokine, macrophage inflammatory protein-1β, matrix metalloprotease, MMP-3, MMP-9, monocyte chemotactic protein-1, monocyte chemotactic protein-4, orexin, thymus, activation-regulated chemokine, tumor necrosis factor-α, kynurenic acid, 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol.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.

Stanley
et al., 2010 [84]
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 β-endorphin, met-enkephalin, dynorphin, serotonin metabolite, 5-HIAA, and dopamine metabolite, HVA were measured.Patients in the NSSI group had lower CSF β-endorphin levels and met-enkephalin when compared with a matched group of patients without NSSI but no difference in dynorphin levels was found between the two groups. Also, metabolite levels did not differ in relation to NSSI.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.
β-endorphin and met-enkephalin, opioids acting upon receptors involved in mediating stress-induced and physical pain analgesia, are all involved in NSSI.

Brundin
et al., 2009 [85]
4 MDD males and 6 MDD females of years old ( ) during the year after a suicide attempt. 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  pg/mL to  pg/mL ( ). Orexin was higher in all patients but one (the mean pairwise increase was  pg/mL). At the second follow-up after one year, mean CSF-orexin was still significantly higher than at the time of the suicide attempt (  pg/mL). 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.

Pitchot
et al., 2008 [86]
28 MDD (19 men and 9 women) inpatients were divided into 13 suicide attempters and 15 nonattemptersNo 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.

Brundin
et al., 2007 [87]
66 patients (with a mean age of ), 32 with MDD, 11 dysthymia and 23 an adjustment disorder after a suicide attempt.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
of orexin levels in normal subjects is large. Also, most of the patients who attempted suicide by intoxication used high amounts of benzodiazepines and several patients also received sedatives during the wash-out period.
Orexin neurotransmission
may be a relevant therapeutic target in the pathogenesis of MDD

Brundin
et al., 2007 [88]
101 suicide attempters (51 male and 50 female with a mean age of ), 31 with MDD, 23 with adjustment disorder, 11 with dysthymia, 14 with depressive syndrome NOS, and 22 with other diagnoses. 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
associated with specific psychiatric symptoms (specifically, inertia and decreased motor activity).

Austin
et al., 2003 [89]
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.

Merali
et al., 2006 [90]
Brain samples were obtained from suicides (24 men of 48. years; 6 women of years) of which 27 with MDD (recurrent episodes), 1 with bipolar disorder—depressed phase, and 2 with psychotic MDD and controls (23 men of .96 years and 14 women of years).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.

Brunner
et al., 2002 [91]
19 inpatient suicide attempters (12 female, 7 male) aged years. 6 patients had MDD (single episode), 3 MDD (recurrent episode), 2 had bipolar disorder, 7 an adjustment disorder, and 1 dysthymic disorder.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.

Caberlotto and Hurd, 2001 [92]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.

Inder
et al., 1997 [93]
45 MDD patients (27 females and 18 males) aged years (34 (75.6%) of the patients had suicidal ideation and 7 had attempted suicide within the current month) compared with 11 healthy controls (4 males and 7 females) aged years. 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.

Olsson
et al., 2004 [94]
13 patients who attempted suicide diagnosed with MDD according to the DSM-III-R criteria.Patients were assessed using
MADRS and the Brief Anxiety Scale (BSA), examined at pretreatment, and followed by every 3 or 4 months.
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.

Westrin
et al., 2001 [95]
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 ( ), whereas CSF—somatostatin was significantly increased ( ) and CSF-CRH had not changed significantly at follow-up.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.

Westrin
et al., 1999 [33]
36 suicide attempters (mean age ), of which 12 with MDD, 12 depressive disorder NOS, 2 dysthymia, and 12 adjustment disorder. 11 patients had made one or more previous suicide attempts. Patients were compared with 36 controls (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 ( ) and CRH and NPY were low ( ) in recent suicide attempters. Patients who had repeatedly attempted suicide had the lowest NPY. A correlation between NPY and cortisol ( ) was found in suicidal patients with depression NOS, whereas beta-END correlated with cortisol ( ) in suicidal MDD patients. A postdexamethasone decrease of NPY was observed only in controls.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.

Westrin
et al., 1998 [96]
34 patients (mean age ), of which 12 had MDD, and 22 other major affective disorders were compared with 34 controls (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.

Westrin
et al., 1998 [97]
A total of 38 suicide attempters (mean age of ) of which 11 with MDD, 12 with adjustment disorder, 10 with depression NOS were compared with 38 controls (mean age of ). 18 had a personality disorder.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.

Roy, 1993 [98]Depressed patients who had attempted and repeated suicide after the 5-year follow-up period.A 5-year follow-up was performedCSF 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

Widdowson et al., 1992 [34]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.

Ordway
et al., 1995 [99]
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.

Träskman-Bendz
et al., 1992 [100]
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.

Scarone
et al., 1990 [101]
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.

Maes
et al., 1989 [102]
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 measuredNo 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.