The neurobiology of depression PALAZIDOU, Eleni
British medical bulletin,
03/2012, Volume:
101, Issue:
1
Journal Article
Peer reviewed
Open access
Depressive disorder is a long term, relapsing condition associated with high levels of disability and mortality. It has a neurobiological basis and is associated with functional and structural brain ...abnormalities.
The data discussed have been obtained mainly from meta-analyses, randomized controlled clinical trials and key review papers as well as animal studies.
Genetic vulnerability and stress are key factors in its aetiopathogenesis. Dysregulation of the hypothalamo-pituitary-adrenal (HPA) axis reduces hippocampal volumes and prefrontal cortex (PFC) activity in depressed patients and disrupts homeostasis within the neurocircuit of depression. Antidepressant drugs increase brain-derived neurotrophin, restoring neuronal growth and activity and modulate interactions between the neurocircuit anatomical structures.
It remains to be confirmed whether structural changes in the brain are purely abnormalities in neuroplasticity and are fully reversible, whether they predate depression and whether they increase in the long term.
Investigation of the molecular mechanisms mediating gene and environment interaction is a growing and potentially fruitful area of research in the neurobiology of depression. Further elucidation of the neuroanatomical and physiological connections between the limbic structures and PFC may help identify key areas to target in treatment. The role of the dysregulation of the HPA axis and identifiable stressors in the recent or remote past which are not always present in depression need further study.
Prospective studies examining the interaction between changes in brain function and structure in relation to stress and identified relevant genes and how these may be influenced by antidepressant drug treatment and the long-term course of depression would help clarify their role in the pathophysiology of this disorder.
The effects of pindolol pretreatment (2 days) on prolactin and cortisol responses to a single dose of (+)-fenfluramine (30 mg po) were examined in nine healthy male volunteers. Pindolol pretreatment ...attenuated the (+)-fenfluramine-induced increase in prolactin concentrations but failed to affect the (+)-fenfluramine-induced cortisol increase. These data provide evidence in support of 5-HT1A receptor involvement in the regulation of prolactin secretion but question its importance in the regulation of cortisol secretion in man.
Lithium medication is the gold standard of treatment in Bipolar Disorder patients, preventing and reducing mood swings and suicidality. However, despite its effectiveness, it is a potentially ...hazardous drug requiring regular monitoring of blood levels to ensure toxic levels are not reached. This paper describes the first steps towards developing a new portable device that can be used by Bipolar Disorder patients to facilitate the analysis of lithium blood levels at home. Solutions of lithium carbonate have been optically fingerprinted using a high-end spectrophotometer. Preliminary measurements indicate that while the visible to near infrared region of the absorption spectra fall heavily within the water band, measurements in the Ultraviolet region show a strong distinction between different lithium concentrations. The optical spectra of Lithium in the 220 nm to 230 nm region demonstrated the ability to differentiate between concentrations representing those found in patients.
We examined 24-hour melatonin rhythms from 20 patients with seasonal affective disorder (SAD) and 20 healthy volunteers. Patients and controls were individually matched for age, sex, and month of ...study. Plasma samples were taken at hourly intervals, and were assayed for melatonin by radio-immunoassay. The 24-hourly melatonin estimations for each individual were fitted to a cosine curve, and the significance of the curve fits was calculated. Two analyses were performed. In analysis 1 the following were calculated: (a) cosine fit, (b) significance of fits, (c) mean amplitude and acrophase (peak) and (d) mean melatonin levels. The curve fits were highly significant for all but three subjects (two patients, one control), but there were no significant differences in any measure between the two groups. In analysis 2 the comparisons were repeated and restricted to the 18 patients and 19 controls in whom there was a statistically significant melatonin rhythm. Again there were no significant differences between groups. These results suggest that the circadian rhythm of melatonin is not abnormal in SAD, and that the therapeutic effect of light in SAD is not mediated by phase shifts in melatonin secretion.
This study was designed to test the hypothesis that patients with SAD have significantly different physiological responses to light than healthy age- and sex-matched controls. We studied retinal ...contrast sensitivity, visual evoked EEG responses, and melatonin suppression by, and cerebral blood flow response to, full-spectrum artificial daylight. There was no significant difference between 10 patients and 11 controls in retinal contrast sensitivity, or amplitude or latency of N2, P2, P100 or P300 on EEG. We compared melatonin suppression in 12 SAD patients and 12 controls. During exposure to 500 lux and 1500 lux artificial daylight both the SAD patients and controls had a significant melatonin percentage suppression; however, the percentage suppression did not differ significantly between the SAD patients and the controls. In addition, we carried out a small pilot study into the effect of light on cerebral blood flow in four SAD patients and four controls. Before exposure to 1500 lux artificial daylight there was no significant difference between patients and controls in global, regional or cerebral hemispheric blood flow. After light exposure the SAD patients and controls had a significantly different percentage change in cerebral blood flow. We suggest that patients with SAD do not have significantly physiological responses to light than controls, except perhaps in cerebral blood flow. Furthermore, mechanisms other than supersensitivity of melatonin suppression must explain both the pathophysiology of the disorder and its response to treatment with light.
Eight patients with endogenous depression who had received no antidepressant treatment for the previous year were treated with the noradrenaline (NA) uptake inhibitor, desipramine (DMI). ...Pre-treatment plasma melatonin concentrations were normal. After one day of DMI treatment plasma melatonin concentrations were increased but the response was impaired compared to normal subjects. The acute effect of DMI on plasma melatonin persisted after six weeks of treatment. These findings question the hypothesis that beta adrenoceptors are supersensitive in depression and that antidepressant drugs act by down-regulating these receptors.
Ten healthy male subjects were treated for three weeks with (+)oxaprotiline, a selective inhibitor of noradrenaline (NA) uptake and with (-)oxaprotiline which does not inhibit NA uptake. Plasma ...melatonin concentrations were measured throughout the night at 0, 1, 7 and 21 days and were higher during treatment with (+)oxaprotiline than with (-)oxaprotiline for the entire three weeks of treatment. Since NA stimulates the production and secretion of melatonin, these results are consistent with a sustained increase in noradrenergic activity within the pineal, during 21 days of treatment with an effective NA uptake inhibitor.
Nocturnal plasma melatonin concentrations were reduced following administration of the alpha 1 adrenoceptor antagonist, prazosin (2 mg orally at 1900h), to 10 normal men. These data indicate that ...alpha 1 adrenoceptors are involved in the physiological control of melatonin secretion in man.
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