A leaky umbrella has little value:evidence clearly indicates the serotonin system is implicated in depression

A recent “umbrella” review examined various biomarkers relating to the serotonin system, and concluded there was no consistent evidence implicating serotonin in the pathophysiology of depression. We present reasons for why this conclusion is overstated, including methodological weaknesses in the review process, selective reporting of data, over-simplification, and errors in the interpretation of neuropsychopharmacological findings. We use the examples of tryptophan depletion and serotonergic molecular imaging, the two research areas most relevant to the investigation of serotonin, to illustrate this

Atypical depression is more common than melancholic in fibromyalgia: an observational cohort study

<p>Abstract</p> <p>Background</p> <p>It has been postulated that atypical and melancholic depression subtypes exist in depressed fibromyalgia (FM) patients, yet no study has empirically tested this hypothesis. The purpose of this study is to determine whether major depressive disorder (MDD) with atypical features and MDD with melancholic features occurs in a FM sample and to describe their demographic, clinical and diagnostic characteristics.</p> <p>Methods</p> <p>An observational cohort study using a descriptive cross-sectional design recruited a convenience sample of 76 outpatients with FM from an academic Rheumatology clinic and a community mental health practice. Diagnoses of FM were confirmed using the 1990 ACR classification guidelines. Diagnoses of MDD and diagnostic subtypes were determined using the DSM-IV-TR criteria. Clinical characteristics were measured using the Fibromyalgia Impact Questionnaire, Structured Interview Guide for the Hamilton Depression Rating Scale with Atypical Depression Supplement and other standardized instruments. Odds ratios were computed on subtype-specific diagnostic criteria. Correlations assessed associations between subtype diagnoses and diagnostic criteria.</p> <p>Results</p> <p>Of the 76 subjects with FM, 11.8% (n = 9) were euthymic, 52.6% (n = 40) met diagnostic criteria for MDD with atypical features and 35.6% (n = 27) for MDD with melancholic features. Groups did not differ on demographic characteristics except for gender (p = 0.01). The non-depressed and atypical groups trended toward having a longer duration of FM symptoms (18.05 yrs. ± 12.83; 20.36 yrs. ± 15.07) compared to the melancholic group (14.11 yrs. ± 8.82; p = 0.09). The two depressed groups experienced greater severity on all clinical features compared to the non-depressed group. The atypical group did not differ clinically from the melancholic group except the latter experienced greater depression severity (p = 0.001). The atypical group demonstrated the highest prevalence and correlations with atypical-specific diagnostic criteria: (e.g., weight gain/ increased appetite: OR = 3.5, p = 0.02), as did the melancholic group for melancholic-specific criteria: (e.g., anhedonia: OR = 20, p < 0.001).</p> <p>Conclusion</p> <p>Depressed fibromyalgia patients commonly experience both atypical and melancholic depressive features; however, in this study, atypical depression was 1.5 times more common than melancholic depression. This finding may have significant research and clinical implications.</p

A leaky umbrella has little value: evidence clearly indicates the serotonin system is implicated in depression.

A recent “umbrella” review examined various biomarkers relating to the serotonin system, and concluded there was no consistent evidence implicating serotonin in the pathophysiology of depression. We present reasons for why this conclusion is overstated, including methodological weaknesses in the review process, selective reporting of data, over-simplification, and errors in the interpretation of neuropsychopharmacological findings. We use the examples of tryptophan depletion and serotonergic molecular imaging, the two research areas most relevant to the investigation of serotonin, to illustrate this

A short history of the 5-HT2C receptor: from the choroid plexus to depression, obesity and addiction treatment

This paper is a personal account on the discovery and characterization of the 5-HT2C receptor (first known as the 5- HT1C receptor) over 30 years ago and how it translated into a number of unsuspected features for a G protein-coupled receptor (GPCR) and a diversity of clinical applications. The 5-HT2C receptor is one of the most intriguing members of the GPCR superfamily. Initially referred to as 5-HT1CR, the 5-HT2CR was discovered while studying the pharmacological features and the distribution of [3H]mesulergine-labelled sites, primarily in the brain using radioligand binding and slice autoradiography. Mesulergine (SDZ CU-085), was, at the time, best defined as a ligand with serotonergic and dopaminergic properties. Autoradiographic studies showed remarkably strong [3H]mesulergine-labelling to the rat choroid plexus. [3H]mesulergine-labelled sites had pharmacological properties different from, at the time, known or purported 5-HT receptors. In spite of similarities with 5-HT2 binding, the new binding site was called 5-HT1C because of its very high affinity for 5-HT itself. Within the following 10 years, the 5-HT1CR (later named 5- HT2C) was extensively characterised pharmacologically, anatomically and functionally: it was one of the first 5-HT receptors to be sequenced and cloned. The 5-HT2CR is a GPCR, with a very complex gene structure. It constitutes a rarity in theGPCR family: many 5-HT2CR variants exist, especially in humans, due to RNA editing, in addition to a few 5-HT2CR splice variants. Intense research led to therapeutically active 5-HT2C receptor ligands, both antagonists (or inverse agonists) and agonists: keeping in mind that a number of antidepressants and antipsychotics are 5- HT2CR antagonists/inverse agonists. Agomelatine, a 5-HT2CR antagonist is registered for the treatment of major depression. The agonist Lorcaserin is registered for the treatment of aspects of obesity and has further potential in addiction, especially nicotine/ smoking. There is good evidence that the 5-HT2CR is involved in spinal cord injury-induced spasms of the lower limbs, which can be treated with 5-HT2CR antagonists/inverse agonists such as cyproheptadine or SB206553. The 5-HT2CR may play a role in schizophrenia and epilepsy. Vabicaserin, a 5-HT2CR agonist has been in development for the treatment of schizophrenia and obesity, but was stopped. As is common, there is potential for further indications for 5-HT2CR ligands, as suggested by a number of preclinical and/or genome-wide association studies (GWAS) on depression, suicide, sexual dysfunction, addictions and obesity. The 5-HT2CR is clearly affected by a number of established antidepressants/antipsychotics and may be one of the culprits in antipsychotic-induced weight gain

Moclobemide effects on prolactin plasma levels in healthy individuals: the hormonal increase induced by a single dose is maintained during a 4-week period of drug intake

Neuroendocrine challenge studies are frequently used to study the pathophysiology of psychiatric illnesses and the effects of psychotropic drug treatment on brain monoamine function. Moclobemide, a reversible inhibitor of monoamine oxidase, with predominant effects on the A-type of the enzyme, was administered to 15 healthy men. Seven out of the 15 also received single blind placebo a week before the moclobemide. the individuals received moclobemide as a single dose (150 mg), followed by doses of 150 mg three times a day, during a 4-week period. Plasma prolactin was measured in the morning over a 150-min period, following the single dose, and then at the end of weeks 1, 2 and 4 of moclobemide intake. the present data show an acute and transitory increase of plasma prolactin levels after the single dose, and also during the long-term moclobemide administration. It might indicate that steady-state moclobemide levels, during the long-term drug administration, were low and thus large fluctuations of drug levels occurred between doses. Thus, it is suggested that larger doses or administering smaller doses more frequently, or both, may induce hyperprolactinaemia with clinical consequences.Universidade Federal de São Paulo, Escola Paulista Med, Dept Psychobiol, BR-04023062 São Paulo, BrazilUniversidade Federal de São Paulo, Escola Paulista Med, Dept Psychobiol, BR-04023062 São Paulo, BrazilWeb of Scienc

Moclobemide effects on prolactin plasma levels in healthy individuals: the hormonal increase induced by a single dose is maintained during a 4-week period of drug intake

Neuroendocrine challenge studies are frequently used to study the pathophysiology of psychiatric illnesses and the effects of psychotropic drug treatment on brain monoamine function. Moclobemide, a reversible inhibitor of monoamine oxidase, with predominant effects on the A-type of the enzyme, was administered to 15 healthy men. Seven out of the 15 also received single blind placebo a week before the moclobemide. the individuals received moclobemide as a single dose (150 mg), followed by doses of 150 mg three times a day, during a 4-week period. Plasma prolactin was measured in the morning over a 150-min period, following the single dose, and then at the end of weeks 1, 2 and 4 of moclobemide intake. the present data show an acute and transitory increase of plasma prolactin levels after the single dose, and also during the long-term moclobemide administration. It might indicate that steady-state moclobemide levels, during the long-term drug administration, were low and thus large fluctuations of drug levels occurred between doses. Thus, it is suggested that larger doses or administering smaller doses more frequently, or both, may induce hyperprolactinaemia with clinical consequences.Universidade Federal de São Paulo, Escola Paulista Med, Dept Psychobiol, BR-04023062 São Paulo, BrazilUniversidade Federal de São Paulo, Escola Paulista Med, Dept Psychobiol, BR-04023062 São Paulo, BrazilWeb of Scienc