Article

Measurement of brain regional alpha-[11C]methyl-L-tryptophan trapping as a measure of serotonin synthesis in medication-free patients with major depression.

Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
Archives of General Psychiatry (Impact Factor: 13.75). 06/2004; 61(6):556-63. DOI: 10.1001/archpsyc.61.6.556
Source: PubMed

ABSTRACT The serotonin hypothesis of depression invokes a relative or absolute deficit of serotonin neurotransmission. Reduced synthesis of serotonin in the brain pathways mediating the expression of mood (ie, the limbic cortex) is a plausible candidate mechanism.
To measure and compare, using the alpha-[(11)C]methyl-l-tryptophan/positron emission tomography method, the brain trapping constant of alpha-[(11)C]methyl-l-tryptophan (K*, milliliters per gram per minute), an index of serotonin synthesis, in brain areas involved in the regulation of mood in patients with major depression (MD) and age- and sex-matched controls.
Between-group comparison.
Department of Psychiatry and Montreal Neurological Institute, McGill University.
Seventeen medication-free outpatients with a current episode of MD (9 women: mean +/- SD age, 41 +/- 11 years; 8 men: mean +/- SD age, 41 +/- 11 years) and 17 controls (9 women: mean +/- SD age, 37 +/- 15 years; 8 men: mean +/- SD age, 32.5 +/- 9.9 years). Main Outcome Measure Normalized K*, normalized to the global mean, was measured in the dorsolateral prefrontal, anterior cingulate, and mesial temporal cortices; the thalamus; and the caudate nucleus.
Compared with age- and sex-matched controls, normalized K* was significantly decreased bilaterally in female patients with MD in the anterior cingulate cortex, in the left anterior cingulate cortex in male patients with MD, and in the left mesial temporal cortex in male and female patients with MD (P<.001 for all). Exploratory analyses identified additional patient-control differences for normalized K* (eg, inferior frontal gyrus and superior parietal lobule), most of which, once corrected for 38 multiple comparisons, lost their significance. Morphometric measurements of the cingulate cortex divisions confirmed that the reduction of normalized K* in depressed patients was not attributable to a reduction in gray matter volume. Normalized K* in the anterior cingulate cortex did not correlate with ratings of depression severity collected at the time of scan.
Reduction of normalized K*, an index of serotonin synthesis, in parts of the limbic and paralimbic cortices may contribute to the biochemical alterations associated with MD.

1 Follower
 · 
80 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: 3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) use may have long-term neurotoxic effects. In the present study, positron emission tomography with the tracer alpha-[11C]Methyl-L-Tryptophan (11C-AMT) was used to compare human brain serotonin (5-HT) synthesis capacity in 17 currently drug-free MDMA polydrug users with that in 18 healthy matched controls. Gender differences and associations between regional 11C-AMT trapping and characteristics of MDMA use were also examined.MDMA polydrug users exhibited lower normalized 11C-AMT trapping in pre-frontal, orbitofrontal and parietal regions, relative to controls. These differences were more widespread in males than in females. Increased normalized 11C-AMT trapping in MDMA users was also observed, mainly in the brain stem and in frontal and temporal areas. Normalized 11C-AMT trapping in the brain stem and (pre)frontal regions correlated positively and negatively, respectively, with greater lifetime accumulated MDMA use, longer durations of MDMA use, and shorter time elapsed since the last MDMA use.Although the possibility of pre-existing 5-HT alterations predisposing people to use MDMA cannot be ruled out, regionally decreased 5-HT synthesis capacity in the forebrain could be interpreted as neurotoxicity of MDMA on distal (frontal) brain regions. On the other hand, increased 5-HT synthesis capacity in the raphe and adjacent areas could be due to compensatory mechanisms.This article is protected by copyright. All rights reserved.
    Journal of Neurochemistry 07/2014; DOI:10.1111/jnc.12826 · 4.24 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Mood disorders have been recognised by the World Health Organization (WHO) as the leading cause of disability worldwide. Notwithstanding the established efficacy of conventional mood agents, many treated individuals continue to remain treatment refractory and/or exhibit clinically significant residual symptoms, cognitive dysfunction, and psychosocial impairment. Therefore, a priority research and clinical agenda is to identify pathophysiological mechanisms subserving mood disorders to improve therapeutic efficacy. During the past decade, inflammation has been revisited as an important etiologic factor of mood disorders. Therefore, the purpose of this synthetic review is threefold: 1) to review the evidence for an association between inflammation and mood disorders, 2) to discuss potential pathophysiologic mechanisms that may explain this association and 3) to present novel therapeutic options currently being investigated that target the inflammatory-mood pathway. Accumulating evidence implicates inflammation as a critical mediator in the pathophysiology of mood disorders. Indeed, elevated levels of pro-inflammatory cytokines have been repeatedly demonstrated in both major depressive disorder (MDD) and bipolar disorder (BD) patients. Further, the induction of a pro-inflammatory state in healthy or medically ill subjects induces 'sickness behaviour' resembling depressive symptomatology. Potential mechanisms involved include, but are not limited to, direct effects of pro-inflammatory cytokines on monoamine levels, dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, pathologic microglial cell activation, impaired neuroplasticity and structural and functional brain changes. Anti-inflammatory agents, such as acetyl-salicylic acid (ASA), celecoxib, anti-TNF-α agents, minocycline, curcumin and omega-3 fatty acids, are being investigated for use in mood disorders. Current evidence shows improved outcomes in mood disorder patients when anti-inflammatory agents are used as an adjunct to conventional therapy; however, further research is needed to establish the therapeutic benefit and appropriate dosage.
    Progress in Neuro-Psychopharmacology and Biological Psychiatry 01/2014; DOI:10.1016/j.pnpbp.2014.01.013 · 4.03 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Molecular imaging is the visualization, characterization, and measurement of biologic processes at the molecular and cellular levels in humans and other living systems. Molecular imaging techniques such as MR spectroscopy and PET have been used to explore the molecular pathophysiology of depression and assess treatment responses. MR spectroscopy is a noninvasive technique that assesses the levels of biochemical metabolites in the brain, while PET uses radioligands injected in the bloodstream that have high binding affinity for target molecules. MR spectroscopy findings suggest a role for glutamate/glutamine and gamma-aminobutyric acid in depression. PET has generally failed to find a correlation between radioligand binding potential and depression severity or treatment response, though it may offer promise in distinguishing responders and nonresponders to treatment. A major challenge for both modalities is that depression is a heterogeneous, multifactorial disorder, while MR spectroscopy and PET are limited to examining a few metabolites or a single radioligand at a time. This difference makes a comprehensive evaluation of neurochemical changes in the brain difficult.
    American Journal of Neuroradiology 05/2014; DOI:10.3174/ajnr.A3965 · 3.68 Impact Factor

Full-text

Download
15 Downloads
Available from
May 22, 2014