Triple Reuptake Inhibitors: The Next Generation of Antidepressants

Depression has been associated with impaired neurotransmission of serotonergic, norepinephrinergic, and dopaminergic pathways, although most pharmacologic treatment strategies for depression enhance only serotonin and norepinephrine neurotransmission. Current drug development efforts are aimed at a new class of antidepressants which inhibit the reuptake of all three neurotransmitters in the hope of creating medications with broader efficacy and/or quicker onset of action. The current review explores limitations of presently available antidepressants and the history and premise behind the movement to devise triple reuptake inhibitors. The evidence for and against the claim that broader spectrum agents are more efficacious is discussed. Examples of triple reuptake inhibitors in development are compared, and preclinical and clinical research with these agents to date is described

DAOA Variants on Diagnosis and Response to Treatment in Patients with Major Depressive Disorder and Bipolar Disorder

OBJECTIVE: This study investigated whether selected D-amino acid oxidase activator ( DAOA) gene single nucleotide polymorphisms (SNPs; rs3916966, rs3916967, rs2391191, rs3916968, rs7139958, rs9558571, rs778293) are associated with major depressive disorder (MDD) and bipolar disorder (BD), and whether they can predict clinical outcomes in Korean in-patients treated with antidepressants and mood stabilizers, respectively. METHODS: In total, 145 patients with MDD, 132 patients with BD and 170 psychiatrically healthy controls were genotyped for the DAOA SNPs. Baseline and final clinical assessments included the Montgomery—Asberg Depression Rating Scale and Young Mania Rating Scale for patients with MDD and BD, respectively. RESULTS: There was no association between DAOA SNP genotypes or alleles with diagnosis, clinical improvement, response rates or remission rates for MDD and BD. Haplotype analyses found no association with MDD or BD diagnosis or clinical outcomes. CONCLUSIONS: The findings suggest that the DAOA SNPs investigated may not affect MDD or BD phenotype, clinical symptoms or other clinical factors, and are unlikely to be involved in MDD or BD development and treatment outcomes. Given the study's limitations, further investigation should be carried out

Investigation of possible epistatic interactions between GRIA2 and GRIA4 variants on clinical outcomes in patients with major depressive disorder

Abstract OBJECTIVES: To investigate the effects of glutamate receptor, ionotropic, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) 2 (GRIA2) rs4260586 and glutamate receptor, ionotropic, AMPA 4 (GRIA4) rs10736648 single nucleotide polymorphisms (SNPs) on response to antidepressants in Korean patients with major depressive disorder (MDD), and to ascertain whether epistatic interactions might exist between these SNPs. METHODS: In this retrospective analysis, patients were assessed at hospital admission and discharge using the Montgomery-Åsberg depression rating scale (MADRS). A multiple regression model was employed to investigate the effects of the two SNP variants on clinical/sociodemographic outcomes relating to MDD. RESULTS: Out of 145 Korean patients, the presence of both GRIA2 rs4260586 and GRIA4 rs10736648 polymorphisms had no significant association with MADRS improvement scores or other clinical/sociodemographic variables. CONCLUSIONS: These data potentially suggest a lack of epistatic interaction between GRIA2 and GRIA4 variants, regarding clinical outcomes in patients with MDD. The study was limited by small sample size, use of different antidepressants and incomplete coverage of genes under investigation. Future research should include larger patient samples treated with different antidepressants, analysis of different SNPs and/or investigation of different gene-gene interactions within the glutamatergic system. KEYWORDS: AMPA 2 (GRIA2), AMPA 4 (GRIA4), Glutamate receptor, epistasis, glutamate receptor, glutamatergic, ionotropic, major depression, single nucleotide polymorphis

Genome-wide association study of antidepressant response: involvement of the inorganic cation transmembrane transporter activity pathway

Description and statistics referred to the SNPs that showed p<0.05 (response phenotype) in both the analyzed samples. (DOC 157 kb

Serotonin-Norepinephrine Reuptake Inhibitors for Pain Control: Premise and Promise

The precise mechanisms of pain perception and transmission in the central nervous system have not been fully elucidated. However, extensive data support a role for the monoamine neurotransmitters, serotonin and norepinephrine, in the modulation of pain. Experiments with animal models of pain indicate that noradrenergic interventions, and to a lesser extent serotonergic interventions, reduce pain-related behavior. This is supported by data from clinical trials in humans in which antidepressants have been shown to reduce pain and functional impairment in central and neuropathic pain conditions. These effects are particularly well-studied in trials with serotonin-norepinephrine reuptake inhibitors (SNRIs), which have provided a useful tool in the clinician’s arsenal, particularly considering the limitations of other classes of pain medications such as opioids, anti-inflammatories, and anticonvulsants (i.e., limited efficacy, safety and tolerability issues). Moreover, painful physical symptoms are frequently comorbid with major psychiatric disorders such as major depressive disorder and anxiety disorders. This paper reviewed and summarized the rationale and potential role of SNRIs for the control of pain including clinical and preclinical background. Currently evidence does not definitely support a role of the SNRIs, while limited data propose a putative promise of SNRIs in the treatment of pain related disorders including fibromyalgia and depressed patients with multiple somatic complaints. More researches are warranted to generalize currently available preliminary evidences

Treatment of Chronic Fatigue Syndrome: Findings, Principles and Strategies

Chronic fatigue syndrome (CFS) is a debilitating condition characterized by serious medically unexplained mental and physical fatigue. The high prevalence and both direct and indirect health costs of CFS patients represent a huge problem for contemporary health care. Moreover, the prognosis of CFS, even when treated, is often poor. In this paper, we first critically review current evidence based treatments of CFS. Second, we discuss the growing insights into the etiopathogenesis of CFS, and the need to translate and integrate these insights into future treatments. In particular, we formulate a pragmatic and empirically testable treatment approach, tailored to the individual needs of patients, which aims at restoring the mental and physical equilibrium of CFS patients by trying to bring about sustained life style changes

Trends in Scientific Literature on Atypical Antipsychotics in South Korea: A Bibliometric Study

ObjectiveaaWe have carried out a bibliometric study on the scientific publications in relation to atypical or second-generation antipsychotic drugs (SGAs) in South Korea. MethodsaaWith the EMBASE and MEDLINE databases, we selected those publications made in South Korea whose title included the descriptors atypic* (atypical*) antipsychotic*, second-generation antipsychotic*, clozapine, risperidone, olanzapine, ziprasidone, quetiapine, sertindole, aripiprazole, paliperidone, amisulpride, zotepine, asenapine, iloperidone, lurasidone, perospirone and blonanserin. We applied some bibliometric indicators of paper production and dispersion with Price’s law and Bradford’s law, respectively. We also calculated the participation index (PI) of the different countries, and correlated the bibliometric data with some social and health data from Korea (such as total per capita expenditure on health and gross domestic expenditure on research and development). ResultsaaWe collected 326 original papers published between 1993 and 2011. Our results state fulfilment of fulfilled Price’s law, with scientific production on SGAs showing exponential growth (correlation coefficient r=0.8978, as against an r=0.8149 after linear adjustment). The most widely studied drugs were risperidone (91 papers), aripiprazole (77), olanzapine (53), and clozapine (43). Division into Bradford zones yielded a nucleus occupied by the Progress in Neuro-Psychopharmacology and Biological Psychiatry (36 articles). A total of 86 different journals were published, with 4 of the first 10 used journals having an impact factor being greater than 4. ConclusionaaThe publications on SGAs in South Korea have undergone exponential growth over the studied period, without evidenc

A 6 Week Randomized Double-Blind Placebo-Controlled Trial of Ziprasidone for the Acute Depressive Mixed State

OBJECTIVE: To examine the efficacy of ziprasidone vs. placebo for the depressive mixed state in patients with bipolar disorder type II or major depressive disorder (MDD). METHODS: 73 patients were randomized in a double-blinded, placebo-controlled study to ziprasidone (40-160 mg/d) or placebo for 6 weeks. They met DSM-IV criteria for a major depressive episode (MDE), while also meeting 2 or 3 (but not more nor less) DSM-IV manic criteria. They did not meet DSM-IV criteria for a mixed or manic episode. Baseline psychotropic drugs were continued unchanged. The primary endpoint measured was Montgomery-Åsberg Depression Rating Scale (MADRS) scores over time. The mean dose of ziprasidone was 129.7±45.3 mg/day and 126.1±47.1 mg/day for placebo. RESULTS: The primary outcome analysis indicated efficacy of ziprasidone versus placebo (p = 0.0038). Efficacy was more pronounced in type II bipolar disorder than in MDD (p = 0.036). Overall ziprasidone was well tolerated, without notable worsening of weight or extrapyramidal symptoms. CONCLUSIONS: There was a statistically significant benefit with ziprasidone versus placebo in this first RCT of any medication for the provisional diagnostic concept of the depressive mixed state. TRIAL REGISTRATION: Clinicaltrials.gov NCT00490542