An open-label trial of the glutamate-modulating agent riluzole in combination with lithium for the treatment of bipolar depression.

BACKGROUND: Preclinical and clinical evidence indicate that the glutamatergic system might play a role in the pathophysiology of mood disorders. This study was conducted to determine the efficacy and safety of riluzole, a glutamate-modulating agent, in bipolar depression. METHODS: This was an 8-week add-on study of riluzole in combination with lithium in acutely depressed bipolar patients aged 18 years and older. After open treatment with lithium for a minimum period of 4 weeks, subjects who continued to have a Montgomery-Asberg Depression Rating Scale (MADRS) score of >/=20 received riluzole (50-200 mg/day) for 8 weeks. RESULTS: Fourteen bipolar depressed patients entered the study. The linear mixed models for total MADRS score showed a significant treatment effect. No switch into hypomania or mania was observed. Overall, riluzole was well tolerated. CONCLUSIONS: Although preliminary, these results suggest that riluzole might indeed have antidepressant efficacy in subjects with bipolar depression.     

某精神科门诊抗抑郁药物应用状况调查

目的：评价某精神科门诊抗抑郁剂的适应症、使用状况。方法：采用自行设计的调查表对2003年度某月北京回龙观医院安定门门诊部就诊患中使用了各种抗抑郁剂的185例患的年龄、性别、诊断、用药种类等情况进行调查。结果：抗抑郁剂主要用于情感性精神障碍(66．5％)，其次是精神分裂症(17．8％)、神经症(12．4％)，少部份用于脑器类精神障碍(2.2％)、进食障碍(1.1％)。采用频度最高的是SSRIS(58．4％)，其次是其他新型抗抑郁剂(22.2％)、传统抗抑郁剂(19.5％)。结论：临床上抗抑郁剂的应用(适应症)范围逐渐扩大，临床已经从传统抗抑郁剂转为以SSRIS及其它新型抗抑郁剂为主流的药物治疗方案。     

Functional anatomical correlates of antidepressant drug treatment assessed using PET measures of regional glucose metabolism

Neurophysiological studies of major depression performed using PET imaging have shown abnormalities of regional cerebral blood flow (CBF) and glucose metabolism in multiple prefrontal cortical and limbic structures that have been more generally implicated in emotional processing. The current study investigated the effects of antidepressant drug treatment in these regions using PET measures of glucose metabolism. Subjects with primary MDD (n=27) were imaged while unmedicated and depressed, and, of these, 20 were rescanned following chronic antidepressant drug treatment. Regional metabolism was compared between unmedicated depressives and controls and between the pre- and post-treatment conditions in regions-of-interest (ROI) where metabolism or flow had previously been shown to be abnormal in unmedicated depressives. At baseline, the mean metabolism was increased in the left and right lateral orbital cortex/ventrolateral prefrontal cortex (PFC), left amygdala, and posterior cingulate cortex, and decreased in the subgenual ACC and dorsal medial/dorsal anterolateral PFC in the unmedicated depressives relative to controls, consistent with the results of previous studies. Following treatment, metabolism significantly decreased in the left amygdala and left subgenual ACC, and corresponding changes in the orbital and posterior cingulate cortices approached significance. The metabolic reduction in the amygdala and right subgenual ACC appeared largely limited to those subjects who both responded to treatment and remained well at 6 months follow-up, in whom the reduction in amygdala metabolism tightly correlated with the reduction in HDRS scores. The magnitude of the treatment-associated, metabolic change in the amygdala also correlated positively with the change in the stressed plasma cortisol levels measured during scanning. These data converge with those from other PET studies to indicate that primary MDD is associated with abnormal metabolism in limbic and paralimbic structures of the mesiotemporal and prefrontal cortices. Chronic antidepressant drug treatment reduces metabolism in the amygdala and ventral ACC in subjects showing a persistent, positive treatment response. In contrast, the persistence of the abnormal metabolic deficits in the dorsomedial/dorsal anterolateral PFC in MDD during treatment may conceivably relate to the histopathological changes reported in these regions in post mortem studies of MDD.     

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.