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Major depressive disorder (MDD) is a heritable disease with a heavy personal and socio-economic burden. Antidepressants of different classes are prescribed to treat MDD, but reliable and reproducible markers of efficacy are not available for clinical use. Further complicating treatment, the diagnosis of MDD is not guided by objective criteria, resulting in the risk of under- or overtreatment. A number of markers of MDD and antidepressant response have been investigated at the genetic, epigenetic, gene expression and protein levels. Polymorphisms in genes involved in antidepressant metabolism (cytochrome P450 isoenzymes), antidepressant transport (ABCB1), glucocorticoid signalling (FKBP5) and serotonin neurotransmission (SLC6A4andHTR2A) were among those included in the first pharmacogenetic assays that have been tested for clinical applicability. The results of these investigations were encouraging when examining patient-outcome improvement. Furthermore, a nine-serum biomarker panel (includingBDNF, cortisol and soluble TNF-α receptor type II) showed good sensitivity and specificity in differentiating between MDD and healthy controls. These first diagnostic and response-predictive tests for MDD provided a source of optimism for future clinical applications. However, such findings should be considered very carefully because their benefit/cost ratio and clinical indications were not clearly demonstrated. Future tests may include combinations of different types of biomarkers and be specific for MDD subtypes or pathological dimensions. [ABSTRACT FROM PUBLISHER]

Prenatal depression affects approximately 10% to 15% of women. Guidelines recommend supporting women to make informed treatment decisions; however, minimal evidence exists regarding this decision-making process. This study aimed to develop a constructivist grounded theory of prenatal antidepressant treatment decision-making. Semi-structured interviews were conducted with purposively sampled women from the community or specialty clinics (N = 31). Iterative data collection and analysis, theoretical sampling, and member checking supported model sufficiency. In the Creating Comfort in Choice theory that we developed, participants were highly conscious of societal stigma toward mental illness and prenatal medication use, so fear, anxiety, and guilt dominated decision-making. Participants navigated dynamically among three clusters of decision-making activities: seeking information, making sense of information, and self-soothing. "Seeking information" included internal and external processes. In "making sense of information," participants appraised available evidence. In "self-soothing," participants engaged in coping strategies to try to alleviate painful emotions. The Creating Comfort in Choice theory can support patient-oriented decision-making regarding prenatal mental healthcare. [ABSTRACT FROM AUTHOR]

Levomilnacipran is a novel serotonin and norepinephrine reuptake inhibitor (SNRI) for the treatment of major depressive disorder. This paper reviews up-to-date data on the pharmacology, short- and long-term efficacy, safety and tolerability of levomilnacipran. The drug differs from previously available SNRIs in having twice the potency for norepinephrine versus serotonin reuptake inhibition. In four of the six short-term clinical trials, levomilnacipran was statistically significantly more efficacious than placebo. The only available relapse prevention study did not show reduction in time to relapse, perhaps because relapse rates were low. The commonest adverse events occurring twice as often as on placebo were nausea, hyperhidrosis, constipation, tachycardia, vomiting, erectile dysfunction, palpitations, and ejaculation disorder. In a few patients, hypertension or orthostatic hypotension may occur. Levomilnacipran has been shown to be effective in the short-term treatment of major depressive disorder and may represent an incremental advance. However, further research about its efficacy in subgroups of patients and comparing it to other antidepressants is needed. [ABSTRACT FROM AUTHOR]

This paper reviews the literature concerning the ethnobotany, phytochemistry, and pharmacology of Mondia whitei, which is also known as Mondia whytei, African ginger or simply as mondia. Mondia is used in many parts of Africa as a traditional remedy to improve appetite and libido, as a galactagogue, as a fertility medication, and as an antidepressant. In African countries, where it is used medicinally, the most commonly cited use is as an aphrodisiac. The scientific studies reviewed in this report employed either in vivo rodent models or isolated organ techniques, and therefore the results cannot be directly extrapolated to humans. Nevertheless, these studies provide scientific evidence that support the traditional uses of mondia as an aphrodisiac and an antidepressant. Based on the safety data available in the literature, mondia is reasonably expected to be safe when prepared and used according to traditional practices. [ABSTRACT FROM AUTHOR]

The section presents summaries of several studies on pain and palliative care pharmacotherapy. The first study provided an understanding of the chronic pain experience by patients. The second study described progress in improved pain management, inequalities in pain treatment and the importance of good pain management education. Another paper discussed the importance and findings in the management of pain in palliative care.

INTRODUCTION: The objective of this study was to compare, in a naturalistic setting, the efficacy and tolerability of selective serotonin reuptake inhibitors (paroxetine, sertraline, citalopram) and venlafaxine, in 120 depressed inpatients. This paper attempts to review which variables may influence a physician's choice of a specific antidepressant for a specific patient. METHOD: Patients were assessed using the Hamilton Psychiatric Rating Scale for Depression (HAM-D), the Montgomery-Åsberg Depression Rating Scale (MADRS), the Clinical Global Impression (CGI) and the Symptoms Check List (SCL-90). The two groups under assessment were comparable in all socio-demographic characteristics. We used logistic regression analyses to identify variables that differentiate the two groups at baseline. This, in turn, would represent those variables with the potential to influence a physician's selection of an antidepressant. RESULTS: Venlafaxine patients reported significantly worse scores on MADRS at baseline, but any difference was no longer present at discharge. We found no significant variation in the efficacy of the antidepressants under study and there were no differences in the incidence and profiles of adverse events between the groups of patients. CONCLUSION: The degree of severity of the actual depressive picture appears to influence choice in favour of venlafaxine. However, it appears that the choice of SSRIs is more closely linked to patients who present a previous history of non-mood psychiatric symptoms. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Reboxetine is the first available selective noradrenaline re-uptake inhibitor (selective NRI). This paper gives an overview of its antidepressant efficacy and tolerability in eight randomized double-blind, multicentre clinical trials. The clinical profile of reboxetine is also compared with that of the tricyclic antidepressants (TCAs) desipramine and imipramine and the selective serotonin re-uptake inhibitor (SSRI) fluoxetine. METHODS: Pooled data were analysed from seven short-term (4 ± 8 weeks) and one long-term (up to 1 year) trials comparing reboxetine with placebo, imipramine, desipramine or fluoxetine. The tolerability of reboxetine was evaluated in 2613 patients with major depression or dysthymia. Data from 1959 patients with major depressive disorder were included to assess drug efficacy. Efficacy was principally assessed using the Hamilton Depression Rating Scale (HAM-D). RESULTS: Reboxetine was more effective than placebo in three of four short-term trials, and it was as effective as fluoxetine, imipramine and desipramine. In long-term treatment, reboxetine was more effective than placebo in preventing relapse (≥ 50% increase in HAM-D) and recurrence (HAM-D total score ≤ 10). In a subset of severely depressed patients, reboxetine was as effective as imipramine and significantly more effective than fluoxetine. Reboxetine was as effective as imipramine in the elderly, but better tolerated. The most common adverse events among the 1503 patients (adults and elderly) who received reboxetine were dry mouth (22%), constipation (15%), sweating (12%) and insomnia (11%). Overall, reboxetine was well tolerated, as well as the SSRI fluoxetine and better than the TCAs imipramine and desipramine. CONCLUSIONS: Reboxetine is effective and well tolerated in the short and long-term treatment of depression. It is as well tolerated as fluoxetine and better than imipramine and desipramine. (Int J Psych Clin Pract 2000; 4: 201 - 208). [ABSTRACT FROM AUTHOR]

Current treatment of major depressive disorder (MDD) warrants critical reexamination. Initial treatment response rates are modest and drop dramatically after 3 months. Meanwhile, MDD is emerging as the leading cause of disease burden worldwide. We searched PubMed (up to June 2021) for randomized controlled trials comparing antidepressant combinations versus monotherapy. We discuss findings from these studies in light of current treatment guidelines for MDD. These recommend a sequence of single, six-week-long, medication trials, before trying antidepressant combinations. The result leaves one third of patients still depressed after six months of treatment. Optimizing the first three months of MDD treatment is crucial because response rates during this period are five times better than in the second three months. We propose a new, evidence-based algorithm of sequential antidepressant treatment steps, termed Accelerated Sequential Antidepressant Protocol (ASAP), that may offer better response rates than current guidelines. ASAP involves shorter duration medication trials (2–4 weeks) and earlier use of antidepressant combinations, seeking additive antidepressant effects without worsening side effects. Future research should compare ASAP to current treatment guidelines. Research is also needed on the role of rapidly acting antidepressants like ketamine for acutely ill and suicidal depressed patients. [ABSTRACT FROM AUTHOR]

Deficiencies in standard of care antidepressants are driving novel drug discovery. A new age of antidepressant medications has emerged with the introduction of rapid-acting antidepressants with efficacy in treatment-resistant patients. The newly approved medicines and those in clinical development for major depressive disorder (MDD) are documented in this scoping review of newly approved and emerging antidepressants. Compounds are evaluated for clinical efficacy, tolerability, and safety and compared to those of standard of care medicines. A new age of antidepressant discovery relies heavily on glutamatergic mechanisms. New medicines based upon the model of ketamine have been delivered and are in clinical development. Rapid onset and the ability to impact treatment-resistant depression, raises the question of the best first-line medicines for patients. Drugs with improvements in tolerability are being investigated (e.g. mGlu2/3 receptor antagonists, AMPA receptor potentiators, and novel NMDA receptor modulators). Multiple companies are working toward the identification of novel psychedelic drugs where the requirement for psychedelic activity is not fully known. Gaps still exist – methods for matching patients with specific medicines are needed, and medicines for the prevention of MDD and its disease progression need research attention. [ABSTRACT FROM AUTHOR]

Objectives: Depressive disorders are severe mental disorders Here, we perform a meta-analysis of the effect of zinc vs. placebo as an adjunct to conventional antidepressants on the scores in the Hamilton Rating Scale for Depression after 6 and after 12 weeks. A systematic literature search found only three such trials (total n = 124 at baseline, n = 103 at 6 weeks (imputed sample size) and n = 103 at endpoint after 12 weeks). We performed random effects meta-analysis We computed a weighted effect size (Hedges' g) for the difference of the absolute scores of the Hamilton Depression Rating Scale between the group given zinc and the group given placebo after 6 and after 12 weeks. We performed subgroup analysis according to whether not it was stated in the original studies that patients in a clinical trial or subgroup within a trial had not reached remission with previous treatment with a standard antidepressant during the same illness episode. After 6 weeks, we obtained the following effect sizes: Overall effect size: Hedges' g = −0.67, p = 0.03. Subgroup with documented non-remission: Hedges' g = − 0.97, p = 0.001. Group without documented non-remission −0.35, p = 0.24. After 12 weeks: Overall effect size: Hedges' g = −1.0, p = 0.03. Subgroup with documented non-remission: Hedges' g = − 1.46, p < 0.001. Group without documented non-remission: Hedges' g = − 0.54, p = 0.07. We provide preliminary evidence for the efficacy of zinc vs. placebo as an adjunct to antidepressant medication. [ABSTRACT FROM AUTHOR]

Duloxetine is a commonly used antidepressant that is a serotonin and norepinephrine reuptake inhibitor. We aimed to investigate the frequency and severity of clinical effects following duloxetine overdose. We undertook a retrospective review of duloxetine overdoses (>120 mg) admitted to two tertiary toxicology units between March 2007 and May 2021. Demographic information, details of ingestion (dose, co-ingestants), clinical effects, investigations (ECG parameters including QT interval), complications (coma [GCS < 9], serotonin toxicity, seizures and cardiovascular effects), length of stay [LOS] and intensive care unit [ICU] admission were extracted from a clinical database. There were 241 duloxetine overdoses (>120 mg), median age 37 years (interquartile range [IQR]: 25–48 years) and there were 156 females (65%). The median dose was 735 mg (IQR: 405–1200 mg). In 177 patients, other medications were co-ingested, most commonly alcohol, paracetamol, quetiapine, diazepam, ibuprofen, pregabalin and oxycodone. These patients were more likely to be admitted to ICU (12 [7%] vs. none; p = 0.040), develop coma (16 [9%] vs. none; p = 0.008) and hypotension [systolic BP < 90 mmHg] (15 [8%] vs. one; p = 0.076). Sixty four patients ingested duloxetine alone with a median dose of 840 mg (180–4200 mg). The median LOS, in the duloxetine only group, was 13 h (IQR:8.3–18 h), which was significantly shorter than those taking coingestants, 19 h (IQR:12–31 h; p = 0.004). None of these patients were intubated. Six patients developed moderate serotonin toxicity, without complications and one had a single seizure. Tachycardia occurred in 31 patients (48%) and mild hypertension (systolic BP > 140 mmHg) in 29 (45%). One patient had persistent sympathomimetic toxicity, and one had hypotension after droperidol. Two patients of 63 with an ECG recorded had an abnormal QT: one QT 500 ms, HR 46 bpm, which resolved over 3.5 h and a second with tachycardia (QT 360 ms, HR 119 bpm). None of the 64 patients had an arrhythmia. Duloxetine overdose most commonly caused sympathomimetic effects and serotonin toxicity, consistent with its pharmacology, and did not result in coma, arrhythmias or intensive care admission, when taken alone in overdose. [ABSTRACT FROM AUTHOR]

Irritable bowel syndrome is a heterogeneous disease with a complex underlying pathophysiology and multiple symptoms - that is, clinical manifestation patterns. As such, management of irritable bowel syndrome requires a flexible approach tailored to the individual patient. This article reviews rational, evidence-based management strategy and treatment options for this variable condition. [ABSTRACT FROM AUTHOR]

This study was designed to investigate possible antidepressant-like effects of the extract prepared from the flowers of Hypericum montbretti Spach. (Guttiferae, Clusiaceae). Phytochemical constituents of the methanolic extract were analysed by HPLC method. The main flavonoid component was detected as rutin, and another highly concentrated phenolic compound was quercitrin. Antidepressant activity of the extract was examined by tail suspension and modified forced swimming tests, whereas the motor coordination of the animals was tested by the Rota-Rod apparatus. Reboxetine at a dose of 20  mg kg−1 was used as a reference drug. Dose-dependent antidepressant activity was observed in both tests following the administration of extract at 100 and 250 mg kg−1 doses. To the best of our knowledge, this is the first study reporting the antidepressant activity of H. montbretti extract. Additionally, the results of this work support previous papers reporting the antidepressant activity of rutin. [ABSTRACT FROM PUBLISHER]

Objectives: The objective of this study was to evaluate the fetal cardiac function in human pregnancies exposed to sertraline (a selective serotonin reuptake inhibitor) compared to unexposed pregnancies.Method: We included 44 women in gestational week 25 + 0 days to week 26 + 6 days. Fifteen women used sertraline (50-150 mg per day), and 29 women used no daily medication. We assessed fetal cardiac function by Myocardial Performance Index (MPI), E/A ratios and by tricuspid and mitral annular plane systolic excursion (TAPSE and MAPSE) measured by 2D M-mode and by 4D eSTIC M-mode.Results: There were no differences between the sertraline exposed and the unexposed. The mean difference of MPI was 0.03 (95% CI -0.08-0.03), of tricuspid and mitral E/A ratios 0.00 (95% CI -0.03-0.05) and 0.03 (95% CI -0.07-0.01), respectively. The mean difference of TAPSE, by 2D and eSTIC, was 0.07 mm (95% CI -0.56-0.41) and 0.10 mm (95% CI -0.55-0.34). Mean difference of MAPSE, by 2D and eSTIC was 0.16 mm (95% CI -0.22-0.53) and 0.24 mm (95% CI -0.16-0.65), respectively. Serum levels of sertraline in exposed participants ranged from 33-266, median 92 nmol/L.Conclusions: We found no significant differences in fetal cardiac function, assessed by TAPSE, MAPSE, MPI and E/A ratios, in pregnancies exposed to sertraline compared to the unexposed. [ABSTRACT FROM AUTHOR]

Background: Originally believed to be an atypical antidepressant acting at serotonin transporters, tianeptine is now known to also be an atypical agonist at mu-opioid receptors. Its nonmedical use may be increasing amidst the broader context of novel drug and supplement use. Objectives: To analyze social-media text from current, former, and prospective tianeptine users for better understanding of their conceptualizations of tianeptine, motives for and patterns of use, and reported benefits and harms. Methods: Reddit posts were obtained and thematically coded; additional quantitative analyses were conducted. Results: A total of 210 posts mentioning tianeptine were made between 2012 and 2020. Eighteen thematic categories were identified, 10 of which were consistent with expected themes. Two independent raters coded all text, generating 1,382 unique codes, of which 1,090 were concordant (78.9% interrater agreement). Tianeptine use was frequently associated with use of other drugs, particularly kratom, phenibut, and racetams. People conceptualized and variously used tianeptine as an opioid, antidepressant, and "nootropic" (cognitive enhancer). Between 2014 and 2020, mentions of positive effects decreased, while mentions of adverse effects and withdrawal increased. Motivations for use included substitution or withdrawal mitigation for other drugs (especially opioids) and for kratom itself; self-treatment for psychiatric symptoms; and improvement of quality of life, mood, or performance. Descriptions of tolerance, withdrawal, and addiction were evident. Intravenous use was rare and strongly discouraged, with detrimental effects described. Conclusion: Tianeptine is recognized as an opioid (though not only an opioid) in online communities. Posts describe benefits, acute risks, and patterns of co-use that warrant greater clinical attention. [ABSTRACT FROM AUTHOR]

Reducing the risk of relapses is a critical component of major depressive disorders treatment. Guidelines suggest maintenance with antidepressant drugs in recurrent depression, but this solution has recently been questioned. The aim of this article is to provide a critical review of the literature of the main treatment options currently available to prevent relapse and recurrence in depression. We compared long-term antidepressant therapy (i.e., indefinite maintenance of antidepressant), intermittent antidepressant therapy (i.e., use of antidepressants mainly limited to the acute phases), use of psychotherapy in the sequential model (i.e., pharmacotherapy in the acute phase and psychotherapy in the residual phase). We argue that the same solution may not apply to all patients and question the feasibility of a single course of treatment in the setting of complex disorders that are encountered in practice. The clinician should weigh advantages and disadvantages in the individual case. The sequential model appears to be particularly indicated in recurrent depression. Relapse is a major challenge of depressive disorders treatment Treatment options currently available include long-term antidepressants, intermittent antidepressants, addition of psychotherapy to pharmacotherapy in the sequential model Maintenance with antidepressants in recurrent depression has recently been questioned The sequential model appears to be particularly indicated in recurrent depression [ABSTRACT FROM AUTHOR]

Introduction: Current antidepressant therapies exhibit low therapeutic efficiency and delayed onset of antidepressant action. Thus, the search for better acting agents is a continuous process. One of the primary targets for the development of new antidepressant drugs is the glutamate N-methyl-D-aspartate (NMDA) receptor. Areas covered: The present review aims to summarize and provide an update on published preclinical data evaluating the antidepressant efficacy of various NMDA antagonists and their mechanisms of action. The review also provides an update on the clinical efficacy of ketamine and esketamine as well as other NMDA receptor antagonists based on published results from clinical studies. Expert opinion: The recent approval of esketamine by the FDA for the treatment of major depressive disorder (MDD) culminates the almost 30 years of research focused on the NMDA receptor as a target for the development of antidepressants. This action gives hope to patients who do not respond to currently available pharmacotherapy. While knowledge of the mechanism of action of ketamine/esketamine will pave the way for the creation of a new class of antidepressants, recent results have shown that several issues regarding the use of these compounds or other NMDA receptor antagonists must be clarified. [ABSTRACT FROM AUTHOR]

Objectives: Whether hippocampal volume predicts response and/or remission after antidepressant treatment of major depressive episodes (MDE) in major depressive disorder (MDD) remains unclear. We meta-analysed prospective studies comparing baseline hippocampal volume in patients with or without response/remission after antidepressant treatment. Methods: Pubmed, Embase and Google Scholar were searched for studies of patients with current MDE in MDD, with hippocampal volume assessments at baseline, initiation of antidepressant drug treatment, and prospective assessment of response/remission after treatment. Results: Six studies (374 patients), of which two were positive and four negative, were meta-analysed. Compared to responders/remitters, patients who failed to achieve response/remission had smaller total hippocampus volumes at baseline (mean volume difference¼260mm3, 95% CI [93; 427], P¼0.002). These results remained significant in patients under 60 years of age (P¼0.02), in those over 60 years old (P¼0.04), and for right (P¼0.006) and left (P¼0.02) hippocampi. The probability of non-response/non-remission was 68.6% for patients with a total hippocampal volume at least 10% lower than the average, and 47.1% for patients with a total hippocampal volume 10% higher than the average. Conclusions: In depressed patients treated with antidepressant drugs, smaller hippocampal volumes predict lower response/remission rates. [ABSTRACT FROM AUTHOR]

Mental health treatment status and antidepressant use were investigated among men and women with an eating disorder (ED) who were interviewed in a general population survey of 3005 adults (aged ≥15 years). Compared to women, men with an ED were significantly less likely to receive treatment for a mental health problem or to be currently using an antidepressant.Onmultivariate analyses, female gender, lower mental health-related quality of life, and lower weight/shape overvaluation were significant predictors of receiving treatment and antidepressant use. Treatment was less likely in men and in people with higher ED cognitions. [ABSTRACT FROM AUTHOR]

Introduction: Countless antidepressant randomized trials were conducted and showed statistically significant benefits of selective serotonin reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake inhibitors (SNRIs) over placebo. Meanwhile, critics are increasing regarding the efficacy of antidepressants in the treatment of MDD because at least a proportion of clinical trials could be hampered by various biases. In contrast, number of failed trials is increasing in the recent years which have made developing psychiatric medications progressively more time-consuming and expensive. Areas covered: Biases and related issues in clinical trials for antidepressants can be identified as an important common contributing factor to the two paradoxical phenomenon. This review identifies possible biases that can occur before, during, and after clinical trials of antidepressant. Expert commentary: Recent studies not only may over-estimate efficacy of antidepressants, but also may exaggerate placebo response because of various biases. Sponsorship and publication biases have been one of the targets of the criticism and ethical debate. Thus, initiating new trend of research by re-organizing academic-industry partnership will be the most important task in the next five years. [ABSTRACT FROM PUBLISHER]

Two new cycloartane glycosides, cyprotusides A (1) and B (2), were isolated from the rhizomes ofCyperus rotundus. Their chemical structures were elucidated on the basis of IR, MS, NMR spectroscopic analyses coupled with chemical degradation. The potential antidepressant activity of the two compounds was evaluated. In the despair mice models, compounds1and2showed significant antidepressant activity. [ABSTRACT FROM PUBLISHER]

Depression is associated with low serum Brain Derived Neurotrophic Factor (BDNF) and elevated levels of serum cortisol. Yoga practices have been associated with antidepressant effects, increase in serum BDNF, and reduction in serum cortisol. This study examined the association between serum BDNF and cortisol levels in drug-naïve patients with depression treated with antidepressants, yoga therapy, and both. Fifty-four drug-naïve consenting adult outpatients with Major Depression (32 males) received antidepressants only (n = 16), yoga therapy only (n = 19), or yoga with antidepressants (n = 19). Serum BDNF andcortisol levels were obtained before and after 3 months using a sandwich ELISA method. One-way ANOVA, Chi-square test, and Pearson’s correlation tests were used for analysis. The groups were comparable at baseline on most parameters. Significant improvement in depression scores and serum BDNF levels, and reduction in serum cortisol in the yoga groups, have been described in previous reports. A significant negative correlation was observed between change in BDNF (pre–post) and cortisol (pre–post) levels in the yoga-only group (r = −0.59,p= 0.008). In conclusion, yoga may facilitate neuroplasticity through stress reduction in depressed patients. Further studies are needed to confirm the findings and delineate the pathways for these effects. [ABSTRACT FROM PUBLISHER]

Anxiety disorders and pregnancy may occur concurrently in some women. Although, several epidemiological or clinical studies about anxiety disorders in pregnancy exist, data on their treatment are very limited. Similar to other anxiety disorders, specific pharmacological treatment approaches in pregnant women with panic disorder (PD) have not been discussed in the literature. An important issue in the treatment of pregnant women with any psychiatric diagnosis is the risk–benefit profile of pharmacotherapy. Therefore, the treatment should be individualized. Untreated PD seems to be associated with several negative outcomes in the pregnancy. When the results of current study regarding the safety of pharmacological agents on the fetus and their efficacy in PD were gathered, sertraline, citalopram, imipramine and clomipramine at low doses for pure PD, and venlafaxine appeared to be more favorable than the other potential drugs. However, controlled studies examining optimum dosing, efficacy of antipanic medications and risk–benefit profile of intrauterine exposure to treated or untreated PD are urgently needed. [ABSTRACT FROM PUBLISHER]

Generalized Anxiety Disorder (GAD) is a persistent condition characterized by chronic anxiety, exaggerated worry and tension, mainly comorbid with Major Depressive Disorder (MDD). Currently, selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors are recommended as first-line treatment of GAD. However, some patients may not respond to the treatment or discontinue due to adverse effects. Vortioxetine (VRX) is a multimodal antidepressant with a unique mechanism of action, by acting as 5-HT3A,5-HT1Dand 5-HT7receptor antagonist, partial agonist at the 5-HT1Aand 5-HT1Breceptors and inhibitor at the 5-HT transporter. Preliminary clinical trials showed contrasting findings in terms of improvement of the anxiety symptomatology and/or cognitive impairment. Here, we aim to systematically review the evidence currently available on the efficacy, safety and tolerability of VRX in the treatment of GAD. The generalizability of results on the efficacy of VRX in patients with anxiety symptomatology and GAD is limited due to few and contrasting RCTs so far available. Only two studies, of which one prevention relapse trial, reported a significant improvement in anxiety symptomatology compared to three with negative findings. [ABSTRACT FROM PUBLISHER]

Antidepressants are widely administered to chronic pain patients, but there is large interindividual variability in their efficacy and adverse effect rates that may be attributed to genetic factors. Studies have attempted to determine the impact of genetic polymorphisms in enzymes and transporters that are involved in antidepressant pharmacokinetics, for example, cytochrome P450 and P-gp. The impacts of genetic polymorphisms in the targets of antidepressants, such as the serotonin receptor or transporter, the noradrenaline transporter and the COMT and monoamine oxydase enzymes, have also been described. This manuscript discusses the current knowledge of the influence of genetic factors on the plasma concentrations, efficacy and adverse effects of the major antidepressants used in pain management. [ABSTRACT FROM AUTHOR]

Due to inadequate efficacy of antidepressants, various new chemical entities and agents of natural origin have been tested for therapeutic efficacy both alone and to augment existing antidepressants, producing varied clinical results. This article summarizes the basic properties of curcumin and its mechanisms of action, with specific emphasis on the etiopathogenesis of depression, preclinical and current clinical evidence, and future research directions, to better understand the possible role of curcumin in treating depression. Curcumin may have antidepressant activities with diverse mechanisms of action involving primarily neurotransmitters, transcription pathways, neurogenesis, the hypothalamic-pituitary-adrenal axis and inflammatory and immune pathways, as demonstrated in various animal and human studies. Current published randomized clinical trials suggest a small, non-significant benefit of curcumin for major depression. More adequately-powered and methodologically improved studies are mandatory. [ABSTRACT FROM AUTHOR]

Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) widely used in the treatment of major depression. It has been detected in surface and wastewaters, being able to negatively affect aquatic organisms. Most of the ecotoxicity studies focused only in pharmaceuticals, though excipients can also pose a risk to non-target organisms. In this work the ecotoxicity of five medicines (three generic formulations and two brand labels) containing the same active substance (fluoxetine hydrochloride) was tested on the algaChlorella vulgaris, in order to evaluate if excipients can influence their ecotoxicity. Effective concentrations that cause 50% of inhibition (EC50) ranging from 0.25 to 15 mg L−1were obtained in the growth inhibition test performed for the different medicines. The corresponding values for fluoxetine concentration are 10 times lower. Higher EC50values had been published for the same alga considering only the toxicity of fluoxetine. Therefore, this increase in toxicity may be attributed to the presence of excipients. Thus more studies on ecotoxicological effects of excipients are required in order to assess the environmental risk they may pose to aquatic organisms. [ABSTRACT FROM AUTHOR]

Sexual dysfunction is a troubling obstacle for individuals being treated for depression and can be caused by both depressive symptoms as well as antidepressant drugs. Selective serotonin reuptake inhibitors (SSRIs) represent a class of antidepressants commonly associated with sexual dysfunction, even after symptomatic improvement. Candidate gene studies have identified associations between sexual dysfunction and altered SSRI pharmacokinetics or to the neurotransmitter systems affected by depression and SSRI treatment. The multifactorial nature of this phenotype and study heterogeneity are currently limitations to the translation of these findings to clinical use. Larger, prospective studies of genetic-guided antidepressant selection may help to clarify the clinical utility of pharmacogenetics in minimizing sexual side effects. [ABSTRACT FROM AUTHOR]

Aim: This study aimed to evaluate the relationship between a human GRIK4 gene polymorphism (rs1954787) and responsiveness to antidepressant treatment in depressed patients. Methods: A meta-analysis was carried out on five studies. Pooled odds ratios (ORs), 95% CIs and a χ2 test measuring heterogeneity were calculated. A test of publication bias was also conducted. Results: Alleles and genotypes from a total of 2169 depressed patients were analyzed. The results showed that the C allele appeared more frequently than the T allele in responders to treatment (OR: 1.22; 95% CI: 1.035-1.445; z = 2.36; p = 0.018). Similarly, CC homozygotes were more likely than TT homozygotes to respond to treatment (OR: 1.45; 95% CI: 1.107-1.913; z = 2.69; p = 0.007). No evidence of publication bias was detected. Conclusion: Subjects possessing the C allele or CC genotype of the GRIK4 polymorphism rs1954787 are more likely to respond to antidepressant treatment relative to subjects harboring the T allele and TT genotype. Additional replication of this result is required before this association can be considered definitive, after which it may become possible to employ this marker in conjunction with other known predictors in order to anticipate the outcomes of treatment with antidepressant medications. Original submitted 25 April 2014; Revision submitted 6 June 2014 [ABSTRACT FROM AUTHOR]

Objective. There is limited information on mirtazapine overdose, but cases of severe effects (seizures, serotonin toxicity and coma) have been reported. We aimed to investigate the clinical effects and complications of mirtazapine overdose. Methods. This was an observational case series of mirtazapine overdoses (> 120 mg) identified from admissions to a toxicology unit between January 1987 and August 2013. Demographic information, details of ingestion, clinical effects, ECG parameters (HR, QT and QRS), and length of stay were extracted from a clinical database. Results. From 267 mirtazapine overdoses, there were 89 single-agent mirtazapine ingestions and 178 cases where mirtazapine was taken with at least one other drug. The median age of the 89 single-agent mirtazapine ingestions was 36 years [interquartile range (IQR): 26-49 years; Range: 15-81 years]; 45 were female (51%). The median ingested dose was 420 mg (IQR: 270-750 mg; Range: 150-1350 mg) and 41 patients (46%) had a Glasgow coma score (GCS) < 15, but the minimum GCS was 10. There were no seizures, serotonin toxicity or delirium. Tachycardia occurred in 29 patients (33%) and hypertension in 32 patients (36%). The median QRS was 80 ms (Range: 80-120 ms) and there were no cases with QT prolongation. There were no arrhythmias and no deaths. The median length of stay was 14 h (IQR: 8.8-18.2 h; Range:2.2-75 h). No single-agent mirtazapine patient was admitted to intensive care. The 178 patients taking co-ingestants had more severe toxicity depending on the co-ingested drug. Conclusion. Mirtazapine appears to be relatively benign in overdose, associated with tachycardia, mild hypertension and mild CNS depression not requiring intervention. [ABSTRACT FROM AUTHOR]

Certain preferences for the timing of daily activities (chronotype) may predispose an individual to sleep problems and mood disorders. In this study, we have examined the link between chronotypes and depression. Participants ( N = 6071) were recruited from a random sample of the general population aged 25 to 74 yrs living in defined geographical areas, as part of the National FINRISK Study in 2007 in Finland. Chronotype assessment was based on six items from the original Horne-Östberg Morningness-Eveningness Questionnaire. Depression was assessed with four self-reported items, including two probes for a diagnosis of a major depressive episode, diagnosed or treated depression, and use of antidepressants. We also analyzed correlations between chronotype and several health indicators, such as systolic and diastolic blood pressures, resting heart rate, weight, and waist circumference. The odds ratios for a range of indicators of depression were higher for evening types (2.7- to 4.1-fold) and intermediate types (1.5- to 1.9-fold) than for morning types. Our results suggest that individuals having a preference for evening hours to carry out their daily activities are prone to depression. (Author correspondence: ilona.merikanto@helsinki.fi) [ABSTRACT FROM AUTHOR]

Tryptizol® [amitriptyline HCl (AT); El-Kahira Pharmacological and Chemical Co., Cairo, Egypt], a widely used antidepressant drug in Egypt, was evaluated for its genotoxicity. The evaluation was performed in somatic (bone marrow) and germ (spermatocytes) cells, as well as well as the sperm morphology (i.e., head and tail) and count of the resulting sperm. Three doses were tested (low, medium, and high); they were chosen according to the drug manufacturer. The low-dose group received orally 1 mg/kg body weight (b.w.) daily for a total period of 1 month; the medium-dose group received 1 mg/kg b.w. daily for 15 days and 2 mg/kg b.w. daily for another 15 days; and the high-dose group received 1 mg/kg b.w. daily for 10 days, then 2 mg/kg b.w. daily for another 10 days and, finally, 4 mg/kg b.w. daily for 10 more days. The results showed that AT treatment induced structural and numerical chromosome abnormalities in somatic cells (bone marrow) and germ cells (spermatocytes). Moreover, AT significantly reduced both the mitotic index and meiotic activity after the different treatments used. AT was found to increase significantly the incidence of sperm-cell head and tail abnormalities. The sperm-cell count was also significantly decreased with the 3 doses tested. In general, results of chromosome abnormalities in both somatic and germ cells as well as sperm morphology and count showed that the effect of AT was dose dependent. The results of the current study showed that AT is a genotoxic agent for both somatic and germ cells and should be taken under special precautions and medical supervision. [ABSTRACT FROM AUTHOR]

Objectives. Epigenetic mechanisms, such as changes in gene expression resulting from chromatin remodeling through histone acetylation, have been implicated in the pathophysiology of depression. However, the antidepressant-like effect of the histone deacetylase inhibitor sodium butyrate (SB) has been inconclusive. The aim of this study was to examine the antidepressant-like effect of SB and elucidate its molecular mechanisms. Methods. We examined the antidepressant-like effect of SB in a forced swim test (FST) and a tail suspension test (TST). Hippocampal gene expression analyses using DNA microarray and real-time PCR were undertaken. Western blotting and ChIP assay were undertaken to examine whether histone acetylation was associated with changes in gene expression by SB. Results. Repeated administration of SB significantly reduced immobility on the FST and the TST, and significantly altered the levels of mRNA for several genes; e.g., upregulation of transthyretin (Ttr) and downregulation of serotonin 2A receptor (Htr2a). Western blotting and ChIP assay revealed selective increases in histone H4 acetylation at the promoter of the Ttr gene with a significant increase in Ttr immunoreactivity 24 h after the final administration of SB. Conclusion. These findings suggest the possibility that alterations in gene expression, including upregulation of Ttr and downregulation of several other genes, including Htr2a, may be involved in antidepressant-like effect of SB. [ABSTRACT FROM AUTHOR]

Antidepressants are reported to display anti-inflammatory effects. Nitric oxide (NO), in turn, has a key role in inflammation. The objective of the present study was to evaluate the effect of amitriptyline co-administered with L-NAME (a NO synthase inhibitor) on certain parameters of acute inflammatory response in rats, as a form to investigate a possible participation of NO in the anti-inflammatory effects of amitriptyline. For this, two animal models were used: carrageenan-induced paw edema and acute peritonitis. In the last one, peritoneal exudate, adhesion molecules expression by peripheral blood leukocytes and serum cytokines levels were evaluated. In a noninflammatory condition, serum levels of nitrates were determined. L-NAME induced a potentiation of the anti-inflammatory effects of amitriptyline ( p < 0.05) in the paw edema model; however, these effects were not abrogated when L-NAME was substituted by L-arginine administration. A decrease in both leukocyte concentration and total number of cells in the peritoneal exudate and a reduction in the total serum levels of nitrates were observed with co-administration of L-NAME and amitriptyline ( p < 0.05). No significant differences among groups were found concerning the expression of adhesion molecules by peripheral blood leukocytes ( p > 0.05). There was a significant decrease on IL-1β and TNF-α serum levels in the experimental groups when compared to the control animals. Together the present results and the literature suggest that the anti-inflammatory effects of amitriptyline may be due to a decrease in NO production. A decrease in IL-1β/TNF-α serum levels may also be implicated in the results observed. [ABSTRACT FROM AUTHOR]

Objectives. Our aim was to perform a meta-analysis of randomized controlled trials comparing efficacy and side effects of bifrontal (BF) ECT to bitemporal (BT) or unilateral (RUL) ECT in depression. Methods. We performed a systematic review of randomized controlled trials comparing BF ECT with RUL or BT ECT in depression. Eight trials ( n = 617) reported some cognitive outcome. Efficacy was measured by reduction in Hamilton Depression Rating Scale score. Cognitive outcomes were limited to Mini-Mental State Examination (MMSE) in seven studies, with two studies measuring each of: Complex-figure delayed recall, Trail-making tests and verbal learning. Results. Efficacy was equal between BF and BT ECT (Hedges's g = 0.102, P = 0.345, confidence interval (CI): -0.110, 0.313) and BF and RUL ECT (standardized mean difference = -0.12, P = 0.365, CI: -0.378, 0.139). Post-treatment MMSE score decline was less for BF than BT ECT ( g = 0.89, CI: 0.054, 1.724) but not RUL ECT. RUL ECT impaired Complex figure recall more than BF ECT ( g = 0.76, CI :0.487, 1.035), but BF ECT impaired word recall more than RUL ECT ( g = -1.45, CI: -2.75, -0.15). Conclusions. Bifrontal ECT is not more effective than BT or RUL ECT but may have modest short-term benefits for specific memory domains. BF ECT has potential advantages, but given longer experience with BT and RUL, bifrontal ECT requires better characterization. [ABSTRACT FROM AUTHOR]

The present study examined the relationship between religiosity/spirituality and treatment response to antidepressant medication (citalopram). One-hundred and forty-eight Caucasian and African-American adults with uncomplicated major depression were treated with citalopram (20-60 mg/day) over an eight-week period in a prospective multi-site clinical trial. Treatment response was assessed weekly with the Hamilton Rating Scale for Depression. Religiosity (i.e., religious behaviours) and spirituality (i.e., spiritual well-being) were assessed at week 3. No significant associations between spirituality and treatment response were found; however, there was a strong curvilinear relationship between religiosity and treatment response. Compared to lower or higher levels of religiosity, a moderate level of religiosity was significantly associated with a higher likelihood of remission and greater reduction in severity of depression. This association was independent of social support, ethnicity, gender, education, and baseline depression severity. A moderate amount of religiosity appears to be independently associated with an enhanced treatment response to citalopram. [ABSTRACT FROM AUTHOR]

Melatonin, N-acetyl-5-methoxytryptamine, the major hormone produced by the pineal gland under the influence of the dark/light cycle, has been shown to have a large number of therapeutic possibilities. It has been utilized in several countries for circadian rhythm disorders, sleep disturbances, jet lag, and sleep–wake cycle disturbances in blind people, and shift workers. In our mechanism of act, the Gi protein-coupled metabotropic melatonin receptors MT1 and MT2 are the primary mediators of the physiological actions of melatonin. This hormone plays an important role in the regulation of physiological and neuroendocrine functions, such as synchronization of seasonal reproductive rhythms and entrainment of circadian cycles. In addition to its chronobiological role, several pharmacological effects of melatonin have been reported in mammals including sedative, antioxidant, anxiolytic, antidepressant, anticonvulsant, and analgesic activities. There is some evidence from clinical trials that melatonin can be helpful in that event. Current trends of pharmacological functions of melatonin pointed out its use in the treatment of neurodegenerative and neoplastic diseases. These effects and uses of melatonin are mentioned but further confirmatory studies are needed in most of them. [ABSTRACT FROM AUTHOR]

Depression, among other mood disorders, represents one of the most common health problems worldwide, with steadily increasing incidence and major socio-economic consequences. However, since the knowledge about the underlying pathophysiological principles is still very scanty, depression and other mood disorders are currently diagnosed solely on clinical grounds. Currently used treatment modalities would therefore benefit enormously from the development of alternative therapeutic interventions. The implementation of proper animal models is a prerequisite for increasing the understanding of the neurobiological basis of mood disorders and is paving the way for the discovery of novel therapeutic targets. In the past thirty years, since the seminal description of the Forced Swim Test as a system to probe antidepressant activity in rodents, the use of animals to model depression and antidepressant activity has come a long way. In this review we describe some of the most commonly used strategies, ranging from screening procedures, such as the Forced Swim Test and the Tail Suspension Test and animal models, such as those based upon chronic stress procedures, to genetic approaches. Finally we also discuss some of the inherent limitations and caveats that need to be considered when using animals as models for mental disorders in basic research. [ABSTRACT FROM AUTHOR]

The aim of the study was to explore the traditional use of Cinnamomum cassia against depression. The standardised methanolic extract of the bark of C. cassia was evaluated for antidepressant activity using various behavioural tests, i.e. tail suspension test (TST), forced swim test (FST) and locomotor activity test. The serotonergic and noradrenergic modulation was assessed using 5-hydroxytryptophan (5-HTP)-induced head twitches and yohimbine potentiation tests, respectively. The fluoxetine and phenelzine were used as positive controls in the study. The C. cassia extract significantly decreased the immobility time in TST (maximum effective dose tested was 50 mg/kg) while no effect was observed in FST and locomotor activity test. The extract significantly increased the 5-HTP-induced head twitches while yohimbine-induced lethality remained unaltered. The aforementioned results are similar to that caused by fluoxetine. The standardised methanolic extract of C. cassia demonstrated antidepressant activity that can be attributed to rise in serotonin levels. [ABSTRACT FROM AUTHOR]

Myrica nagi Hook (syn. Myrica esculenta Buch. & Ham) (Myricaceae) is commonly known as box berry. The bark of Myrica nagi is used in the treatment of mental illness by different ethnic groups of the rural region of Orissa (India). In the present work, the anxiolytic and antidepressant effects of an ethanol extract of M. nagi were analyzed at three different dosages (100, 200, and 400 mg/kg, p.o.) by elevated plus-maze, light/dark exploration test, tail suspension test, and the forced swimming model. Oral administration of the ethanol extract (100, 200, and 400 mg/kg, p.o.) of M. nagi showed significant (p < 0.01) and dose-dependent anxiolytic activity by increasing time spent in the open arms of the elevated plus-maze and in the lit box indicating an anxiolytic effect. Nevertheless this treatment was unable to exhibit an effect identical to antidepressants in the tail suspension and forced swimming tests. Altogether, these results suggest an anxiolytic effect of the ethanol extract of M. nagi. [ABSTRACT FROM AUTHOR]

This open-label multicentre semi-naturalistic study in Finland assessed the impact of educational information on efficacy of 16-week treatment with escitalopram (5-20 mg/day) in a patient population suffering from depression. Patients were randomized single blind to receive educational information (n=79) or no information (n=78) in addition to open-label escitalopram treatment. Patients were assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS), Clinical Global Impression - Severity and - Improvement (CGI-S and CGI-I), Patient Global Evaluation (PGE), and Hopkins Symptom Checklist (SCL-90) scales. Tolerability was assessed by the incidence of adverse events (AEs). A total of 132 (84%) out of 157 patients completed the study, with similar completer rates in both groups. There was no statistically significant effect of educational information on the efficacy of escitalopram treatment, as measured by MADRS, CGI and PGE. Mean MADRS total score was 25.3 at baseline, corresponding to moderate to severe depression, and decreased to 7.9 at the end of the treatment for both groups. The response rate (≥50% reduction in MADRS total score from baseline) was 80% at the end of treatment for both groups. The clinical relevance of the improvement was seen in CGI-I and PGE scores and there was a strong correlation between the two scales, indicating agreement by both patients and investigators. AEs were mostly mild and transient and 11 patients (7.0%) dropped out of the study due to AEs, with similar incidence in both groups. Escitalopram was effective and well tolerated in the treatment of depression over a 16-week period in a semi-naturalistic setting, and an additional effect of educational information could not be shown, possibly due to the high response to treatment. [ABSTRACT FROM AUTHOR]

There are three non-tricyclic dual serotonin (5-HT) and noradrenaline (NA) reuptake inhibitors (SNRIs) currently used in human therapeutics for psychiatric disorders. These medications differ in their in vitro potency to inhibit 5-HT and NA reuptake with differential ratios of activity. Using in vivo studies carried out in laboratory animals, which better reflect human physiology than experiments using lysed tissue in a test tube, venlafaxine is about three times more potent on 5-HT than NA reuptake, duloxetine five times, and milnacipran is about twice more potent on NA than 5-HT reuptake. Sustained administration of SNRIs induces different adaptive effects on presynaptic 5-HT and NA receptors controlling the function of 5-HT and NA neurons, suggesting that they may differentially affect transmission of these two neuronal systems. In the treatment of depression, SNRIs appear to have similar effectiveness and when compared to selective 5-HT reuptake inhibitors, they generally exert a superior antidepressant effect. Taken together, these observations suggest that individual patients not responding to a SNRI may present a favourable response to another agent within that family. SNRIs have different pharmacokinetic properties and exert distinct effects on the activity of liver metabolic enzymes. These features of SNRIs can help clinicians tailor treatment to individual patients. [ABSTRACT FROM AUTHOR]

Medication algorithms have been used extensively in treating psychiatric patients, while geographic variations among these reflect the local history of the practice of psychiatry in each region. Here we review algorithms used for mood disorders in Japan in terms of their utility, problems, and possible future development. The first Japanese algorithm for mood disorders was completed in 1997 by the Japanese Psychopharmacology Algorithm Project (JPAP). Development of the JPAP algorithm was evidence-based, giving major but not exclusive weight to clinical trial outcomes. Unlike others, the JPAP algorithm suggests possible addition of a benzodiazepine to first-line antidepressant treatment for major depression. When the first-choice antidepressant fails, the algorithm recommends monotherapy with another antidepressant over "add-on" therapy. Clinical problems with the JPAP algorithm include lack of guidance concerning how to change from one drug to another. Psychiatry in Japan provides less formal structure for post-graduate education and undertakes less communication with the general public than in many countries. This makes use of an algorithm important for improving quality of practice, provided that clinicians remain aware of the advantages, limitations, and problems of algorithms. [ABSTRACT FROM AUTHOR]

Dizziness is the most commonly reported symptom of abrupt discontinuation from the selective serotonin reuptake inhibitor (SSRI) category of antidepressants. The reported dizziness is exacerbated by even slight head movement, and therefore is likely to be vestibular in origin. The SSRIs most implicated are those with short half-lives and which are most selective for serotonin (as opposed to noradrenaline), e.g. paroxetine and sertraline. Since the vestibular nucleus complex (VNC) has an abundance of serotonin receptors, the abrupt withdrawal from an SSRI is likely to have a substantial impact on the electrophysiological activity of neurons within it. Here we suggest that the abrupt withdrawal from an SSRI is likely to cause a sudden decrease in serotonin in the VNC, which will disrupt the function of VNC neurons bilaterally, causing dizziness without vertigo. [ABSTRACT FROM AUTHOR]