Selective Serotonergic Antidepressants Research Articles

New-generation, non-SSRI antidepressants: Drug-drug interactions and therapeutic drug monitoring. Part 2: NaSSAs, NRIs, SNDRIs, MASSAs, NDRIs, and others.

After the development of "classical" tricyclic antidepressants and monoamine oxidase inhibitors, numerous other classes of antidepressant drugs have been introduced onto the market. The selective serotonin reuptake inhibitor class is the best-known one, but many others exist, usually identified by their mechanism of activity. In this second part of the review, focused on new-generation antidepressants not included among selective serotonin reuptake inhibitors, the following classes are considered: noradrenergic and selective serotonergic antidepressants; norepinephrine reuptake inhibitors; serotonin, norepinephrine and dopamine reuptake inhibitors; melatonergic agonists and selective serotonergic antagonists; norepinephrine and dopamine reuptake inhibitors; and so forth. These different mechanisms underlie tolerability and safety profiles that can be very different among the classes, with each one providing significant advantages and disadvantages in comparison with others. The main characteristics of the following antidepressants are described: mianserin, mirtazapine, setiptiline, reboxetine, viloxazine, teniloxazine, atomoxetine, nefazodone, agomelatine, bupropion, esketamine, and tianeptine. The paper is focused on their metabolism and interactions, but also includes brief notes on analytical methods useful for their therapeutic drug monitoring.

New-Generation, Non-SSRI Antidepressants: Therapeutic Drug Monitoring and Pharmacological Interactions. Part 1: SNRIs, SMSs, SARIs

New-generation antidepressants (NGAs) are the latest additions to the clinician's arsenal in the fight against depression. After the introduction of selective serotonin reuptake inhibitors (SSRIs), a plethora of other groups followed, identified by their main mechanisms of activity: serotonin and norepinephrine reuptake inhibitors (SNRI); serotonin modulators and stimulators (SMS); serotonin antagonists and reuptake inhibitors (SARI); noradrenergic and selective serotonergic antidepressants (NaSSA); norepinephrine reuptake inhibitors (NeRI); serotonin, norepinephrine and dopamine reuptake inhibitors (SNDRI) or triple reuptake inhibitors (TRI); and melatonin and serotonin agonists (MaSA). Although SSRIs are still the most widely used and well known NGAs, the other groups are increasingly being used in the current therapeutic settings obtaining comparable clinical results, and with tolerability and safety profiles that can often provide significant advantages over those of SSRIs. Scopus and PubMed databases were searched for the most significant papers centered on the medicinal chemistry, pharmacodynamics, pharmacokinetics and analysis in human biological fluids of the following antidepressants: venlafaxine, duloxetine, milnacipran, trazodone, vortioxetine, vilazodone. The main characteristics of commercially available non-SSRI NGAs (belonging to the SNRI, SARI and SMS classes) are described, focusing on the role of analytical methods that can be applied to perform therapeutic drug monitoring (TDM), but also including drug pharmacokinetics, metabolism and interactions.

Comparison of the efficacy of the multimodal serotonergic antidepressants trazodone and vortioxetine in the treatment of patients with endogenous depression: A meta-analysis of double-blind randomized placebo-controlled trials

Selective serotonergic antidepressants with a miltimodal mechanism of action are a new group of antidepressants, which includes trazodone and vortioxetine. Data on the efficacy of trazodone and vortioxetine in treating endogenous depression (major depressive disorder) appear to be rather uncertain now. There have been no direct comparative trials of the efficiency of therapy with trazodone and vortioxetine. Objective : to compare the efficiency of therapy with trazodone and vortioxetine in treating patients with endogenous depression on the basis of statistical generalization of the results of studies of the efficacy of each antidepressant alone. Material and methods. On the basis of the selection criteria, 7 double-blind, randomized, placebo-controlled trials of the efficiency of therapy with trazodone or vortioxetine in patients with endogenous depression were chosen from the PubMed database. The trials were divided into 2 groups according to the comparability of original samples of patients, methods for evaluating their state, and duration of follow-up. The efficiency of therapy with trazodone and that of vortioxetine were compared by determining the statistical significance of differences in the ratio of responders/nonresponders or remitters/nonremitters in Groups 1 and 2 separately. Results. 1) Comparison of the values of 8-week therapy efficiency in Group 1: a) therapy with trazodone at an average dose of about 300 mg/day significantly more frequently results in the alleviation of depressive symptoms to the level of classifying patients into the category of responders than that with vortioxetine at an average dose of about 9 mg/day; b) therapy with trazodone at an average dose of about 300 mg/day significantly more often relieves depressive symptoms to the level of classifying patients into a category of remitters than that with vortioxetine at average dose of about 9 mg/day; c) therapy with trazodone at an average dose of about 300 mg/day and that with vortioxetine at an average dose of about 18.5 mg/day lead to the comparable reduction of depressive symptoms to the level of referring patients to a category of responders or remitters. 2) Comparison of the values of of 6-week treatment efficacy in Group 2: therapy with trazodone at an average dose of about 300 mg/day is statistically significantly less frequently accompanied by the attenuation of depressive symptoms to the level of assigning patients to a category of responders than that with vortioxetine at average dose of about 7.5 mg/day. The validity of the results of comparing the efficiency of therapy in Group 2 is constrained by incomplete comparability of the clinical and demographic characteristics of initial patient samples. Conclusion . The findings suggest the higher efficacy of trazodone 300 mg/day versus vortioxetine 5–10 mg/day and the comparable efficacy of trazodone 300 mg/day and vortioxetine 15–20 mg/day in treating patients with endogenous depression.

Multimodal serotonergic antidepressants

Based on the original literature, the author for the first time describes a history of selective serotonergic antidepressants simultaneously inhibiting the serotonin reuptake and directly interacting with serotonin receptors. A history of creation and introduction of their main representatives is presented. A history of investigation of their neurochemical activity is analyzed in details. The history of the evolution of their classifications is systemized. The data presented suggest the rationale for unifying all selective serotonergic antidepressants, simultaneously inhibiting the serotonin reuptake and directly interacting with serotonin receptors (trazodone, etoperidone, nefazodone, vilazodone, vortioxetine), in one group of 'multimodal serotonergic antidepressants'. The expediency to include this group in the modern neurochemical classification of nootropic drugs is substantiated.

Classification of psychotropic drugs: Problems, solutions, and more problems.

Byline: T. Sathyanarayana Rao, Chittaranjan. Andrade The current classification of drugs was introduced by the World Health Organization in 1976.[sup][1],[2] This classification is known as the ATC system, where A refers to the anatomical site of action (e.g., the central nervous system [CNS]), T refers to the therapeutic indication (e.g., the treatment of depression), and C refers to the chemical class of the drug (e.g., selective serotonin reuptake inhibitor [SSRI]). In the ATC classificatory system, the anatomical site of action could be the CNS (e.g., carbamazepine), the respiratory system (e.g., salbutamol), the cardiovascular system (e.g., digoxin), the gastrointestinal system (e.g., omeprazole), and so on. A problem here is that, for example, antimicrobials and antineoplastic drugs do not act on a specific anatomical system; however, they do act at a specific anatomical target, such as bacterial or neoplastic cells. Vitamins are other examples of drugs that are hard to classify with regard to an anatomical target. For Level 1 CNS drugs, Level 2 includes analgesics, anesthetics, antiepileptics, anxiolytics, antidepressants, antipsychotics, antidementia drugs, mood stabilizers, hypnotics, and others. A problem here is that drugs are classified according to the original indication for which they were studied and approved. However, many drugs have many indications. For example, SSRIs have demonstrated efficacy in depression, generalized anxiety disorder, panic disorder, social anxiety disorder, posttraumatic stress disorder, obsessive-compulsive disorder (OCD), premenstrual dysphoric disorder, migraine (prophylaxis), and other conditions. Nevertheless, SSRIs are still classified as antidepressants. Similarly, antipsychotics such as aripiprazole are effective in schizophrenia, in mania, as antidepressant augmentation treatment in major depressive disorder, as SSRI augmentation treatment in OCD, and in the treatment of delirium. Quetiapine and lurasidone are specifically effective as monotherapy for bipolar depression, and quetiapine is effective as monotherapy for generalized anxiety disorder. Some of these are not approved indications but are indications for off-label use. In like manner, antiepileptics such as valproate are effective in epilepsy, bipolar disorder, pain syndromes, migraine prophylaxis, aggression, anxiety, tardive movement disorders, and other labeled or off-label indications. For Level 1 CNS drugs and Level 2 antidepressants, Level 3 includes monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRIs), noradrenaline reuptake inhibitors, noradrenergic and selective serotonergic antidepressants, and other drugs. Here, the method of classification is a little unsystematic, for example, whereas MAOI, SSRI, and SNRI are mechanisms, TCA describes a structure. Terms such as “newer” antidepressants tell us nothing about the drugs. Classifying Antipsychotic Drugs The problem is greater with the antipsychotic drugs. In the early decades, it was convenient to classify these drugs, based on structure, as phenothiazines, butyrophenones, diphenylbutylpiperidines, and other drugs. With subsequent drug development, many agents were synthesized that had no other member in their group. However, around the same time, a change in adverse effect profile spawned the atypical/typical distinction and usage, and afterward, the older/newer and first/second/third generation antipsychotic terminologies. A problem here is that some of the older antipsychotics did not produce much extrapyramidal adverse effects (EPS), if at all, and were, therefore, atypical in action; thioridazine is an example. In contrast, risperidone, ziprasidone, aripiprazole, blonanserin, and many other newer antipsychotics do produce considerable dose-dependent EPS and akathisia. …

Noradrenaline (Norepinephrine) and Depression

In the pharmacological treatment of depression the focus has recently shifted from serotonin (5-hydroxytryptamine; 5-HT) to noradrenaline (norepinephrine), with the advent of new antidepressants such as noradrenaline reuptake inhibitors, noradrenergic and selective serotonergic antidepressants, and serotonin/noradrenaline reuptake inhibitors. It has been suggested that noradrenergic compounds may prove to have beneficial activity in those depressions that are characterised by a ‘noradrenergic deficiency syndrome’, which is clinically manifested through emotional withdrawal, psychomotor retardation, as well as concentration and memory deficits. The role of noradrenergic mechanisms in the aetiology of depression has been assumed since the catecholamine hypothesis, based on the inhibitory action of tricyclic antidepressants and monoamine oxidase inhibitors on noradrenaline uptake, was formulated. In this article, the aetiological significance of noradrenaline in depression is discussed with regard to the anatomical basis of the noradrenergic system (the locus caeruleus), noradrenaline metabolites, noradrenergic receptors, some aspects of thyroid function and the hypothalamic-pituitary-adrenal axis. The efficacy and tolerability profiles of new antidepressant compounds reboxetine, milnacipran, mirtazapine and venlafaxine are discussed in view of their noradrenergic activity.

Response to venlafaxine in a previously antidepressant treatment-resistant combat veteran with post-traumatic stress disorder

Post-traumatic stress disorder (PTSD) is frequently treated with antidepressant medications, especially the newer selective serotonergic antidepressants which have documented efficacy in PTSD. Analogous to depression, however, some PTSD patients may not have a satisfactory response to these agents. This case report describes a PTSD patient who did not respond to several serotonergic antidepressants, but did improve with venlafaxine which has both noradrenergic and serotonergic properties.