News
Researchers' data from the United States, Argentina and France advance depression research
Data on depression are outlined in reports from the United States, Argentina and France. Study 1: Atypical antipsychotics (APDs) may augment the therapeutic efficacy of SSRIs by potentiation of increased cortical dopamine and norepinephrine concentrations.
According to a study from the United States, "APDs, e.g. olanzapine and risperidone, have been reported to be effective adjunctive treatment for depression if selective serotonin (5-HT) reuptake inhibitors (SSRIs) alone are ineffective. We utilized microdialysis in awake, freely moving rats to study the effect of risperidone in combination with citalopram, an SSRI, on extracellular 5-HT, dopamine (DA), and norepinephrine (NE) efflux in rat medial prefrontal cortex (mPFC)."
M. Huang and colleagues, Psychiatric Hospital at Vanderbilt, explained, "Risperidone (1.0 mg/kg, s.c.), given alone, significantly increased 5-HT, DA, and NE concentrations in the mPFC. Citalopram (10 mg/kg, s.c.), by itself, produced a significant increase in 5-HT levels only. The combination of risperidone and citalopram produced significantly greater increases in efflux of both DA and NE than risperidone alone. However, the effect of this combination on extracellular 5-HT concentrations was not significantly different than that of citalopram alone. The augmentation of DA and NE efflux induced by risperidone plus citalopram could be partially blocked by the selective 5-HT1A antagonist, WAY 100635 (0.2 mg/kg, s.c.).
"The results suggest that the ability of atypical APDs to augment the therapeutic efficacy of SSRIs in major depression and treatment-resistant depression may be due, at least in part, to potentiation of SSRI-induced increases in cortical DA and NE."
The researchers concluded, "The contributions of 5-HT1A receptor stimulation and 5-HT2A and alpha2 adrenergic receptor antagonism to this augmentation are discussed."
Huang and colleagues published their study in Psychopharmacology (Augmentation by citalopram of risperidone-induced monoamine release in rat prefrontal cortex.
Study 2: Fluoxetine treatment restored neuroplasticity-related hippocampal alterations of diabetic mice.
According to recent research from Argentina, "Cerebral dysfunctions, including a high incidence of depression, are common findings in human type 1 diabetes mellitus. An association between depression and defective hippocampal neurogenesis has been proposed and, in rodents, antidepressant therapy restores neuronal proliferation in the dentate gyrus. Hippocampal neurogenesis is also deficient in diabetic mice, which led us to study whether the selective serotonin reuptake inhibitor fluoxetine influences cell proliferation in streptozotocin-diabetic animals."
J. Beauquis and colleagues working with the National Research Council Argentina explained, "Diabetic and control C57BL/6 mice received fluoxetine (10 mg/kg/day, i.p., 10 days) and dentate gyrus cell proliferation was measured after a single injection of 5-bromo-2'-deoxyuridine (BrdU)."
They discovered, "Diabetic mice showed reduced cell proliferation. Fluoxetine treatment, although having no effect in controls, corrected this parameter in diabetic mice. The phenotype of newly generated cells was analyzed by confocal microscopy after seven daily BrdU injections, using Tuj-1/beta-III tubulin as a marker for immature neurones and glial fibrillary acidic protein for astrocytes."
"In controls," continued investigators, "the proportion of Tuj-1-BrdU-positive cells over total BrdU cells was similar to 70%. In vehicle-treated diabetic mice, immature neurones decreased to 56% and fluoxetine brought this proportion back to control values without affecting astrocytes. Therefore, fluoxetine preferentially increased the proliferation of cells with a neuronal phenotype. In addition, neurones were counted in the hilus of the dentate gyrus; a 30% decrease was found in diabetic mice compared with controls, whereas this neuronal loss was prevented by fluoxetine."
The researchers concluded, "Fluoxetine treatment restored neuroplasticity-related hippocampal alterations of diabetic mice. These findings may be potentially important to counteract diabetes-associated depression in humans."
Beauquis and colleagues published their study in European Journal of Neuroscience (Reduced hippocampal neurogenesis and number of hilar neurones in streptozotocin-induced diabetic mice: reversion by antidepressant treatment. Eur J Neurosci, 2006;23(6):1539-1546).
For additional information, contact F. Saravia, National Research Council of Argentina, Institute Biology & Med Experimental, Laboratory Neuroendocrine Biochemistry, Obligado 2490, RA-1428 Buenos Aires, DF, Argentina.
Study 3: A mathematical model for paroxetine antidepressant may be useful for clinical trials.
"Although selective 5-HT reuptake inhibitors (SSRIs) block monoamine uptake within hours of administration to patients, their full clinical effect does not appear until 2-4 weeks after treatment onset," scientists in France report.
"Pindolol, a betablocker with weak partial 5-HT1A receptor agonist activity has been shown to produce a more rapid onset of antidepressant action of SSRIs," wrote B. Gruwez and colleagues, Cochin Hospital. "However, the optimal dosing schedule of pindolol remains controversial.
"Building on a set-point model described previously for the hypothermic effect of 5-HT agonists, we have developed a model based on the concept of homeostatic control mechanisms, in which SSRIs exert their antidepressant effect by increasing the transduction set-point of the postsynaptic 5-HT1A receptor, and pindolol exerts its effect by increasing the rate of feedback mechanisms."
The authors explained, "The predictive distribution of the proportion of responders at each day of measurement (based on population simulation from the model) was not significantly different from the proportions observed in two published clinical trials, one with fluoxetine, the other with paroxetine alone or combined with pindolol.
"The model was applied to the simulation of paroxetine response (clinical score) time course with or without pindolol, after administration of different doses of each drug."
"The simulated total scores on the MADR scale obtained after treatment with paroxetine alone (20 mg/day) or paroxetine (20 mg/day) with different doses of pindolol (1.5, 7.5 and 37.5 mg/day) support that the reason for inconstant pindolol efficacy is that the 7.5 mg dose is too low," reported the authors.