Overweight and obesity affect treatment response in major depression.

BACKGROUND: Epidemiologic and clinical studies suggest comorbidity between major depressive disorder (MDD) and obesity. To elucidate the impact of weight on the course of depression beyond comorbidity, we investigated psychopathology, attention, neuroendocrinology, weight change, and treatment response in MDD patients, depending on their weight. METHODS: Four hundred eight inpatients with MDD participated in the Munich Antidepressant Response Signature Study, designed to discover biomarkers and genotypes that are predictive for clinical outcome. Psychopathology and anthropometric parameters were monitored weekly in 230 patients. In subsamples, combined dexamethasone-corticotropin-releasing hormone and attention tests were conducted at admission and discharge. One thousand twenty-nine diagnosed matched controls served for morphometric comparisons. RESULTS: Patients with MDD had a significantly higher body mass index (BMI) compared with healthy controls. Patients with high BMI (> or =25) showed a significantly slower clinical response, less improvement in neuroendocrinology and attention, and less weight gain than did patients with normal BMI (18.5 < or = BMI < 25) during antidepressant treatment. CONCLUSIONS: Our findings suggest that overweight and obesity characterize a subgroup of MDD patients with unfavorable treatment outcome.     

Neurobiology of antidepressant withdrawal: implications for the longitudinal outcome of depression

Inappropriate discontinuation of drug treatment and noncompliance are a leading cause of long-term morbidity during treatment of depression. Increasing evidence supports an association between depressive illness and disturbances in brain glutamate activity, nitric oxide synthesis, and γ-amino butyric acid. Animal models also confirm that suppression of glutamate N-methyl-D-aspartate receptor activity or inhibition of the nitric oxide-cyclic guanosine monophosphate pathway, as well as increasing brain levels of γ-amino butyric acid, may be key elements in antidepressant action. Imaging studies demonstrate, for the most part, decreased hippocampal volume in patients with depression, which may worsen with recurrent depressive episodes. Preclinical models link this potentially neurodegenerative pathology to continued stress-evoked synaptic remodeling, driven primarily by the release of glucocorticoids, glutamate, and nitric oxide. These stress-induced structural changes can be reversed by antidepressant treatment. In patients with depression, antidepressant withdrawal after chronic administration is associated with a stress response as well as functional and neurochemical changes. Preclinical data also show that antidepressant withdrawal evokes a behavioral stress response that is associated with increased hippocampal N-methyl-D-aspartate receptor density, with both responses dependent on N-methyl-D-aspartate receptor activation. Drawing from both clinical and preclinical studies, this article proposes a preliminary molecular perspective and hypothesis on the neuronal implications of adherence to and discontinuation of antidepressant medication.     

Controlled comparison of milnacipran and fluoxetine in major depression

The efficacy and the tolerance of milnacipran (100 mg/day), a second generation antidepressant which equipotently inhibits both noradrenaline and serotonin reuptake, was compared to fluoxetine (20 mg/day), a selective serotonin reuptake inhibitor, in two parallel groups of, respectively, 97 and 93 major depressive outpatients. The duration of the study was 6 weeks, with assessments every 2 weeks by means of the Montgomery and Asberg depression scale (MADRS), the Hamilton depression scale, the clinical global impressions (CGI), and a checklist of symptoms and side-effects. Results showed significant superiority of fluoxetine over milnacipran on most rating instruments: MADRS (P=0.01) including five individual items, Hamilton depression scale (P=0.002) including ten individual items, CGI of severity (P=0.01) and therapeutical index (P=0.002). On visual analogue scales assessing the clinical profile of the compounds, fluoxetine was rated as exhibiting more psychostimulating activity than milnacipran (P=0.0008). The tolerance of the two antidepressants was very similar, with the exception of symptoms of dizziness which were more frequently reported with milnacipran (P=0.01). These differences in efficacy favoring fluoxetine could result from the selection of a dose of milnacipran below the optimal therapeutic dose for this type of psychiatric patients or to the administration of the compounds in single daily intakes, whereas milnacipran possesses a plasma elimination half-life of only 7 h.     

Les bases de pharmacologie fondamentale du système sérotoninergique : application à la réponse antidépressive

If serotonin (5-hydroxytryptamin [5-HT]) is well known for its role in mood regulation, it also impacts numerous physiological functions at periphery. Serotonin is synthetized at the periphery into the gut by intestinal enterochromaffin cells and in the central nervous system (CNS) in the raphe nucleus from the essential amino acid tryptophan. Physiological effects of 5-HT are mediated by about 15 serotoninergic receptors grouped into seven broad families (5-HT₁, 5-HT₂, 5-HT₃, 5-HT₄, 5-HT₅, 5-HT₆, 5-HT₇ receptor families). Except 5-HT₃ receptor, a ligand-gated ion channels, all the others are G protein-coupled receptors. Serotonin's homeostasis involves serotoninergic autoreceptor such as 5-HT_1A, 5-HT_1B, 5-HT_1D, the enzymatic degradation of serotonin by monoamine oxidase A (MAO-A), and a transporter (serotoninergic transporter [SERT]). In the CNS, the SERT is a key target for various antidepressant drugs such as Selective Serotonin Reuptake Inhibitors (SSRI), Serotonin Norepinephrin Reuptake Inhibitors (SNRI) and tricyclics family. However, antidepressant activity of SERT inhibitors is not directly mediated by the SERT inhibition, but a consequence of postsynaptic 5-HT receptor activation following the increase in 5-HT levels in the synaptic cleft. In pharmacology, SSRIs are defined as indirect agonist of postsynaptic receptor. Among all the 5-HT receptors, 5-HT_1A, 5-HT_1B, 5-HT_1D, 5-HT_2B and 5-HT₄ receptors activation would mediate antidepressant effects. In the meanwhile, 5-HT_2A, 5-HT_2C, 5-HT₃, 5-HT₆ and 5-HT₇ receptors activation would induce opposite effects. The best serotoninergic antidepressant would directly activate 5-HT_1A, 5-HT_1B, 5-HT_1D, 5-HT_2B and 5-HT₄ and would block 5-HT_2A, 5-HT_2C, 5-HT₃, 5-HT₆ and 5-HT₇ receptor. If the chemical synthesis of such a compound may be compromised, SERT inhibition associated with the blockade of some but not all 5-HT receptor could shorten onset of action and/or improve antidepressant efficacy on the overall symptomatology of depression.     

绿萼梅提取物对小鼠的抗抑郁作用

目的：观察绿萼梅提取物对小鼠的抗抑郁作用。方法采用悬尾实验（ TFT）、强迫游泳（ FST）等体内药效评价方法观察绿萼梅醇提取物和水提取物对抑郁模型小鼠的治疗作用。结果绿萼梅醇提物能明显缩短小鼠悬尾和强迫游泳不动时间（ P＜0．05）,且对自主活动无影响（ P＞0．05）;而水提物对小鼠悬尾和强迫游泳不动时间无显著影响（ P＞0．05）。结论绿萼梅乙醇提取物具有抗小鼠抑郁作用。     

A case report on elderly psychotic-like symptoms caused by antidepressant discontinuation

ObjectivesCure for severe depression in elderly patients with psychotic symptoms should consider not only the results of major depression but also the nature of antidepressants and their side effects. Psychiatric disability is higher in patients who have greater deterioration in neurological function.MethodsIn addition to reviewing antidepressant discontinuation syndrome and depressive disorder, this study describes an elderly woman with mild depression that developed into major depression, related to high suspicion of delirium, diagnosed based on patient history, physical health examination, neurological examinations, family history, and laboratory data, with subsequent treatment plan.ResultsThe treatment results and prognosis indicate that patients with paroxetine antidepressant deactivation may enable early use of low-dose quetiapine with less anticholinergic and extrapyramidal side effects for the treatment of depression in elderly patients with psychotic symptoms. The poor prognostic factors for patients were chronic environmental stress (poverty) and lack of a social support system. Although the patient lived with her children and grandchildren, she rarely received care. Hence, it was not possible to monitor her condition and medication intake.ConclusionsThe consensus is that the abrupt discontinuation of short half-life selective serotonin reuptake inhibitors (SSRIs), such as paroxetine can be associated with transient symptomatology, much of which is of a serotonergic nature. Psychotic-like symptoms have also been reported in both controlled trials and large patient databases.     

Antidepressant Therapy (Imipramine and Citalopram) for Irritable Bowel Syndrome: A Double-Blind,Randomized, Placebo-Controlled Trial

Background The efficacy of antidepressants in irritable bowel syndrome (IBS) is controversial. No trials have directly compared a tricyclic with a selective serotonin reuptake inhibitor. Our aim was to determine whether imipramine and citalopram are efficacious in IBS. Methods This was a randomized, double-blind, placebo-controlled, parallel group pilot trial with imipramine (50 mg) and citalopram (40 mg). Results Of 51 IBS patients randomized, baseline characteristics were comparable among the treatment arms; the majority was diarrhea-predominant. Adequate relief of IBS symptoms (primary endpoint) was similar for each treatment arm. Improvements in bowel symptom severity rating for interference (P = 0.05) and distress (P = 0.02) were greater with imipramine versus placebo, but improvements in abdominal pain were not. There was a greater improvement in depression score (P = 0.08) and in the SF-36 Mental Component Score (P = 0.07), with imipramine. Citalopram was not superior to placebo. Approximately 20% of the variance in scores was explained by treatment differences for abdominal pain, bowel symptom severity disability, depression and the mental component of the SF-36. Conclusion Neither imipramine nor citalopram significantly improved global IBS endpoints over placebo.