Reduced orexin levels in the cerebrospinal fluid of suicidal patients with major depressive disorder

https://doi.org/10.1016/j.euroneuro.2007.01.005Get rights and content

Abstract

Orexins are neuropeptides selectively expressed in a small number of neurons in the lateral–posterior hypothalamus. We measured orexin-A in the cerebrospinal fluid (CSF) of 66 patients with major depressive disorder (MDD), dysthymia and adjustment disorder after a suicide attempt. Blood samples confirmed that the patients were free from antidepressive and neuroleptic medication at the time of the lumbar punctures. CSF levels of orexin-A were significantly lower in patients with MDD than in patients with adjustment disorder and dysthymia. Orexin correlated significantly with CSF levels of somatostatin, delta sleep inducing peptide-like immunoreactivity (DSIP-LI) and corticotrophin releasing factor (CRF), but not with leptin or vasopressin. Plasma levels of thyroid-stimulating hormone (TSH) were not reduced in MDD patients, and did not correlate with CSF-orexin. Our results suggest that suicidal patients with MDD have distinct neurobiological features, involving compromised levels of hypothalamic peptides regulating the state of arousal.

Introduction

Suicide is a major cause of death worldwide (Bertolote et al., 2004). Disturbances of sleep, vigilance and appetite are hallmarks of severe depression and suicidality (Singareddy and Balon, 2001). Hypothalamic peptides are likely to significantly influence these behavioural symptoms. Subgroups of patients with major depressive disorder (MDD) exhibit disturbed hypothalamic–pituitary–adrenal (HPA)-axis and there is comorbidity between chronic stress and certain types of depression (Swaab et al., 2005).

Dogs with the neurological condition narcolepsy have been found to have mutations in the orexin receptor gene (Lin et al., 1999), and orexin knockout mice display similar symptoms (Chemelli et al., 1999). Narcolepsy is a disabling condition where the affected individuals among other symptoms suffer from excessive daytime sleepiness and severe disturbances of the sleep pattern. Human patients with narcolepsy have low to undetectable levels of orexin in the cerebrospinal fluid (CSF) (Peyron et al., 2000, Nishino et al., 2001). Taken together, these findings demonstrated that orexins have an important role for regulation of sleep and state of arousal.

Neurons containing orexin have widespread projections to many CNS regions, including hormonal centres in the hypothalamus. Several interactions with hormones in the HPA-axis have been demonstrated (Spinazzi et al., 2006). Levels of CSF-orexin have been measured in different neurological conditions. In addition to narcolepsy, orexin can be affected in subarachnoid haemorrhage and other conditions with a trauma to the hypothalamus (Baumann et al., 2005). There are also reports of low levels of orexin in patients with neurodegenerative diseases affecting the hypothalamus, such as Niemann–Pick's disease (Vankova et al., 2003) and some cases of Parkinson's disease (Drouot et al., 2003).

Although disturbances of vigilance and appetite are common in psychiatric disorders, only few studies to date have investigated orexin in psychiatric patients. We have recently shown that low CSF-orexin levels correlate with more pronounced symptoms of inertia and slowness of movement, as investigated in a cohort of 100 patients with different psychiatric diagnoses (Brundin et al., 2006). In the same study, we found that patients with low CSF-orexin levels were rated as more globally ill, using the Comprehensive Psychiatric Rating Scale (Asberg et al., 1978). In another study, CSF-orexin was measured in 15 patients with unipolar and bipolar disorder (Salomon et al., 2003). The patients were found to exhibit a reduced diurnal variation of orexin. Nishino et al. (2002) have reported an association between orexin levels and sleep latency in 13 schizophrenic patients.

The aim of the present study was to investigate CSF-orexin A in suicidal patients with different psychiatric diagnoses. We were also interested in examining whether orexin levels were correlated with other factors involved in regulation of sleep and appetite in suicidal patients.

Section snippets

Overall design of the study

This study was approved by the Lund University Medical Ethics Committee. Patients gave a written informed consent to participate in the research program. Seventy-six patients were admitted to the University Hospital after a suicide attempt, between 1987 and 2001. They were recruited to the study from the emergency room, the medical intensive care unit, or from a general psychiatric ward. The patients did not receive any antidepressive or neuroleptic medication during a wash-out period

CSF-orexin and mood disorders

Orexin levels in CSF were significantly lower in patients with MDD than in patients with dysthymia or adjustment disorder (one-way ANOVA, p = 0.001, followed by Bonferoni–Dunn's post hoc-test, which yielded p < 0.01 for comparison with adjustment disorder and p < 0.01 for comparison with dysthymia). The mean orexin level was 195 ± 24 pg/ml (mean ± 1 SD) in patients with MDD, 219 ± 21 pg/ml in patients with dysthymia and 213 ± 20 pg/ml in patients with adjustment disorder (Fig. 1).

Orexin and suicidality

There was no difference in

Discussion

We analysed CSF orexin-A in 66 patients who recently attempted to commit suicide. The orexin level was significantly lower in the group of patients with MDD than in patients with adjustment disorder and dysthymia. Orexin correlated significantly with CSF-levels of somatostatin, DSIP-LI and CRF, three other hypothalamic peptides involved in the regulation of sleep and appetite. We have previously shown that these three peptides are significantly reduced in suicidal MDD patients (Traskman-Bendz

Role of the funding source

This study has been performed with the support of research grants from the Swedish Research Council, the Sjöbring foundation and the province of Scania state grants (ALF).

Contributors

Lena Brundin, MD, specializing in psychiatry at Lund University Hospital since 2004. PhD in 2001, Lund University. Responsible for study design, data analysis and manuscript. Expertise area neurobiology, neuroimmunology. Lil Träskman-Bendz, MD, specialist in psychiatry. Professor of psychiatry at Lund University. Responsible for study design, data collection and manuscript. Expertise area suicidology, hypothalamic changes in depression and suicide. Åsa Petersén, MD, specializing in psychiatry

Conflict of interest

The authors have no financial relationships that might bias their work.

Acknowledgements

Research nurse Charlotta Sunnqvist at the Division of Psychiatry, Lund University, is greatly acknowledged for her technical expertise. Professor Rolf Ekman at Gothenburg University and professor Bo Ahrén at Lund University, as well as their laboratories, are greatly acknowledged for their assistance in the analyses of the neuropeptides. We thank professor Patrik Brundin, Lund University, for helpful suggestions and advice.

References (37)

  • American Psychiatric Association

    Diagnostic and Statistical Manual of Mental Disorders

    (1987)
  • M. Asberg et al.

    CPRS—the comprehensive psychopathological rating scale

    Acta Psychiatr. Scand., Suppl.

    (1978)
  • C.R. Baumann et al.

    Normal CSF hypocretin-1 (orexin A) levels in dementia with Lewy bodies associated with excessive daytime sleepiness

    Eur. Neurol.

    (2004)
  • C.R. Baumann et al.

    Hypocretin-1 (orexin A) deficiency in acute traumatic brain injury

    Neurology

    (2005)
  • A.T. Beck et al.

    Classification and nomenclature

  • J.M. Bertolote et al.

    Psychiatric diagnoses and suicide: revisiting the evidence

    Crisis

    (2004)
  • L. Brundin et al.

    Orexin and psychiatric symptoms in suicide attempters

    J. Affect. Disord.

    (2006)
  • X. Drouot et al.

    Low levels of ventricular CSF orexin/hypocretin in advanced PD

    Neurology

    (2003)
  • Cited by (168)

    View all citing articles on Scopus
    View full text