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Aim: The aim of this paper is to clarify the inconsistent findings in the association between antidepressant use and the risk of epithelial ovarian cancer (EOC). Methods: This study is a meta‐analysis of observational studies retrieved from the PubMed, EMBASE, and Web of Science databases prior to August 15, 2017. Two researchers independently screened studies and extracted study characteristics and risk estimates. The odds ratios (OR) and 95% confidence intervals (CI) of EOC risk were summarized using an inverse variance weighted random‐effects model. Heterogeneity between studies was assessed with the I2 statistic. Results: Eight case–control studies involving 7878 EOC cases and 73 913 controls were identified. Compared with non‐use, use of antidepressants was not significantly associated with EOC risk (summarized OR = 1.10, 95% CI: 0.91–1.32, I2 = 74.4%). Similar null results were also observed in the use of selective serotonin reuptake inhibitors (OR = 1.04, 95% CI = 0.80–1.35), tricyclic antidepressants (OR = 1.01, 95% CI = 0.79–1.30), and other antidepressant drugs (OR = 0.91, 95% CI = 0.74–1.12). Subgroup analyses of study characteristics, stratified by the type of control subjects, geographic location, exposure assessment, number of cases, and adjustment for potential confounders, showed that the ORs were broadly consistent across strata. The OR per 1 year‐increment of duration was 0.99 (95% CI = 0.94–1.05, I2 = 40.0%, P = 0.154). Additionally, the OR for the greatest intensity of antidepressant use compared with never use was 0.82 (95% CI = 0.70–0.98, I2 = 0%, P = 0.489). Furthermore, no evidence of publication bias was detected through Funnel plots as well as Egger's and Begg's tests. Conclusions: There is no association between antidepressant use and EOC risk. Further prospective studies are warranted to confirm these findings. [ABSTRACT FROM AUTHOR]

Background: Our knowledge of the broader impacts of antidepressant withdrawal, beyond physical side effects, is limited. Further research is needed to investigate the lived experiences of withdrawal, to aid clinicians on how to guide patients through the process. Aim: To explore antidepressant users' experiences and views on the withdrawal process and how it affected their quality of life across multiple life domains. Design and Setting: We conducted in‐depth qualitative interviews with 20 individuals from the community who had attempted to withdraw from Serotonin Reuptake Inhibitor antidepressants in the past year. Method: Semi‐structured interviews were conducted online. A topic guide was used to ensure consistency across interviews. The interviews were audio‐recorded and transcribed verbatim and analysed using inductive reflexive thematic analysis. Results: Five themes were generated. The first highlighted the challenges of managing the release from emotional blunting and cognitive suppression following antidepressant discontinuation. The second related to the negative impact of withdrawal on close relationships and social interactions. The third showed that concurrent with negative physical symptoms, there was a positive impact on health (exercise was reported by some as a coping mechanism). The fourth theme focused on support from GPs and families, emphasising the importance of mental health literacy in others. The final theme underscored the importance of gradual and flexible tapering in enabling a manageable withdrawal experience, and the consideration of timing. Conclusion: The lived experience of withdrawal significantly impacts individuals' well‐being. Participants emphasised that withdrawal is not just about physical side effects but also affects their emotional, cognitive, and social functioning. Patient and Public Involvement (PPI): Eight people attended individual online meetings to share their experiences of antidepressant withdrawal to help inform the study design and recruitment strategy. Insights from these meetings informed the development of the topic guide. Questions about GP involvement, family relationships, and mood and thinking changes were included based on this PPI work. This ensured the inclusion of topics important to antidepressant users and facilitated the researcher's questioning during the interviews. [ABSTRACT FROM AUTHOR]

In this study, the effects of antidepressants on large‐scale brain networks and the neural basis of individual differences in response were explored. A total of 41 patients with major depressive disorder (MDD) and 42 matched healthy controls (HCs) were scanned by resting‐state functional magnetic resonance imaging separately at baseline and after a 12‐week follow‐up. The patients with MDD received escitalopram for 12 weeks. After treatment, patients were classified into those with MDD in remission [MDDr, endpoint 17‐item Hamilton Depression Rating Scale (HAMD) total score ≤7] and those in nonremission (MDDnr). The human Brainnetome Atlas was used to define large‐scale networks and compute within‐ and between‐network resting‐state functional connectivity (rsFC). Results showed the decreased subcortical network (SCN)–ventral attention network (VAN) connectivity at baseline increased in patients with MDD after 12‐week treatment, and it was comparable with that of HCs. This change was only observed in patients with MDDr. However, the decreased within‐network rsFC in SCN and default mode network (DMN) persisted in all patients with MDD, including those with MDDr and MDDnr, after treatment. The strength of SCN–VAN connectivity at baseline was significantly negatively correlated with the reduction rate of HAMD score in all patients with MDD. Thus, SCN–VAN connectivity may be an antidepressant target associated with depressive state changes and a predictor of treatment response to serotonin reuptake inhibitors. The within‐network rsFC in SCN and DMN may reflect a trait‐like abnormality in MDD. These findings provide further insights into the mechanism of antidepressants and their individual differences in response. The trial name is "Appropriate technology study of MDD diagnosis and treatment based on objective indicators and measurement" (URL: http://www.chictr.org.cn/showproj.aspx?proj=21377; registration number: ChiCTR‐OOC‐17012566). [ABSTRACT FROM AUTHOR]

Aim: While evidence‐based antidepressant treatment is available for major depressive disorder, standard approaches for discontinuation of antidepressants after remission have not yet been established. Decision aids are structured clinical tools that facilitate shared decision‐making between patients and healthcare providers. This study aimed to describe the development process and acceptability of decision aids for major depressive disorder following discontinuation of antidepressant treatment after remission. Methods: We systematically developed a decision aids according to the International Patient Decision Aid Standards. First, a decision aids prototype was created using the results of a systematic review and meta‐analysis previously conducted to identify the consequences of continuing and discontinuing antidepressant treatment. Second, a mixed‐methods questionnaire (alpha acceptability testing) was administered to patients and healthcare providers to improve the decision aids prototype and develop it into a final version acceptable for clinical settings. Results: Our decision aids consisted of a description of major depressive disorder, the option to continue or discontinue antidepressant treatment, the advantages and disadvantages of each option, the consequences of each option, and value clarification exercises for each option. The patients (n = 22) reported that the decision aids had acceptable language (91%), adequate information (91%), and a well‐balanced presentation (95%). Healthcare providers (n = 20) provided favorable feedback. The final decision aids fulfilled all six International Patient Decision Aid Standards qualifying criteria. Conclusion: We successfully developed a decision aids for discontinuation of antidepressant treatment after remission, which could be used during the shared decision‐making process. Further studies are needed to verify the effects of using the decision aids during the shared decision‐making process. [ABSTRACT FROM AUTHOR]

α2‐Adrenoceptors, subdivided into α2A, α2B, and α2C subtypes and expressed in heart, blood vessels, kidney, platelets and brain, are important for blood pressure, sedation, analgesia, and platelet aggregation. Brain α2C‐adrenoceptor blockade has also been suggested to be beneficial for antipsychotic action. However, comparing α2‐adrenoceptor subtype affinity is difficult due to significant species and methodology differences in published studies. Here, 3H‐rauwolscine whole cell binding was used to determine the affinity and selectivity of 99 α‐antagonists (including antidepressants and antipsychotics) in CHO cells expressing human α2A, α2B, or α2C‐adrenoceptors, using an identical method to β and α1‐adrenoceptor measurements, thus allowing direct human receptor comparisons. Yohimbine, RX821002, RS79948, and atipamezole are high affinity non‐selective α2‐antagonists. BRL44408 was the most α2A‐selective antagonist, although its α1A‐affinity (81 nM) is only 9‐fold greater than its α2C‐affinity. MK‐912 is the highest‐affinity, most α2C‐selective antagonist (0.15 nM α2C‐affinity) although its α2C‐selectivity is only 13‐fold greater than at α2A. There are no truely α2B‐selective antagonists. A few α‐ligands with significant β‐affinity were detected, for example, naftopidil where its clinical α1A‐affinity is only 3‐fold greater than off‐target β2‐affinity. Antidepressants (except mirtazapine) and first‐generation antipsychotics have higher α1A than α2‐adrenoceptor affinity but poor β‐affinity. Second‐generation antipsychotics varied widely in their α2‐adrenoceptor affinity. Risperidone (9 nM) and paliperidone (14 nM) have the highest α2C‐adrenoceptor affinity however this is only 5‐fold selective over α2A, and both have a higher affinity for α1A (2 nM and 4 nM, respectively). So, despite a century of yohimbine use, and decades of α2‐subtype studies, there remains plenty of scope to develop α2‐subtype selective antagonists. [ABSTRACT FROM AUTHOR]

Major depressive disorder is a leading cause of disability worldwide. Because conventional therapies are ineffective in many patients, novel strategies are needed to overcome treatment‐resistant depression (TRD). Limiting factors of successful drug development in the last decades were the lack of (1) knowledge of pathophysiology, (2) translational animal models and (3) objective diagnostic biomarkers. Here, we review novel drug targets and drug candidates currently investigated in Phase I–III clinical trials. The most promising approaches are inhibition of glutamatergic neurotransmission by NMDA and mGlu5 receptor antagonists, modulation of the opioidergic system by κ receptor antagonists, and hallucinogenic tryptamine derivates. The only registered drug for TRD is the NMDA receptor antagonist, S‐ketamine, but add‐on therapies with second‐generation antipsychotics, certain nutritive, anti‐inflammatory and neuroprotective agents seem to be effective. Currently, there is an intense research focus on large‐scale, high‐throughput omics and neuroimaging studies. These results might provide new insights into molecular mechanisms and potential novel therapeutic strategies. [ABSTRACT FROM AUTHOR]

Aim: Pharmacotherapy is the primary treatment strategy in major depression. However, two‐thirds of patients remain depressed after the initial antidepressant treatment. Augmented cognitive behavioral therapy (CBT) for pharmacotherapy‐resistant depression in primary mental health care settings proved effective and cost‐effective. Although we reported the clinical effectiveness of augmented CBT in secondary mental health care, its cost‐effectiveness has not been evaluated. Therefore, we aimed to compare the cost‐effectiveness of augmented CBT adjunctive to treatment as usual (TAU) and TAU alone for pharmacotherapy‐resistant depression at secondary mental health care settings. Methods: We performed a cost‐effectiveness analysis at 64 weeks, alongside a randomized controlled trial involving 80 patients who sought depression treatment at a university hospital and psychiatric hospital (one each). The cost‐effectiveness was assessed by the incremental cost‐effectiveness ratio (ICER) that compared the difference in costs and quality‐adjusted life years, and other clinical scales, between the groups. Results: The ICERs were JPY −15 278 322 and 2 026 865 for pharmacotherapy‐resistant depression for all samples and those with moderate/severe symptoms at baseline, respectively. The acceptability curve demonstrates a 0.221 and 0.701 probability of the augmented CBT being cost‐effective for all samples and moderate/severe depression, respectively, at the threshold of JPY 4.57 million (GBP 30 000). The sensitivity analysis supported the robustness of our results restricting for moderate/severe depression. Conclusion: Augmented CBT for pharmacotherapy‐resistant depression is not cost‐effective for all samples including mild depression. In contrast, it appeared to be cost‐effective for the patients currently manifesting moderate/severe symptoms under secondary mental health care. [ABSTRACT FROM AUTHOR]

Aim: We previously demonstrated that intracerebroventricular injection of resolvin D2 (RvD2), a bioactive lipid mediator derived from docosahexaenoic acid, ameliorated depression‐like behavior in lipopolysaccharide‐induced and chronic mild stress–induced mouse models of depression. In the present study, we examined the antidepressant effect of RvD2 on chronic pain–induced depression‐like behavior. Methods: To prepare the neuropathic pain model, mice were subjected to surgery for unilateral spared nerve injury. Two weeks after surgery, the antidepressant effect of RvD2 was examined using the tail suspension test. Results: Chronic pain significantly increased immobility time, and this depression‐like behavior was attenuated by intracerebroventricular injection of RvD2 (10 ng). No effect of RvD2 on the locomotor activity was observed. Conclusion: RvD2 produces an antidepressant effect in a murine model of chronic pain–induced depression and may be a promising lead for the development of novel antidepressants. [ABSTRACT FROM AUTHOR]

Fluoxetine is an antidepressant medicine causing relaxation and mood improvement in people, with silencing certain personality traits in some cases. The question arise if such phenomena can be observed in nontarget organisms such as fish. Fluoxetine affects fishes behavior; however, it is not known if the medicine affects its "personality." This study aimed to evaluate the reaction of the invasive Neogobius fluviatilis and native Gobio gobio individuals to fluoxetine at environmental concentration of 360 ng/L. We prepared three variants of the experiments: (a) behavioral trials with unexposed fishes, (b) behavioral trials with the same fishes after 21 days of fluoxetine exposure, and (c) behavioral trials with the same fishes after 21-day depuration period, that is, without fluoxetine. The fishes reaction time (RT), that is, difference in time spent on reaching food with and without the necessity of overcoming the obstacle, was analyzed. Additionally, the personality, bold or shy, traits of each fish individual, was assigned. The results indicated that environmental concentrations of the antidepressant influenced RT. The average RT of the fishes cultured with fluoxetine was by 7-min shorter in comparison with the nonexposed control. Share of individuals exposed to fluoxetine assigned as bold raised to 71.4% in comparison with 46.4% in nonexposed control. This sheds new light on wild fishes behavior caught from freshwater. Environmental concentrations of the antidepressant influenced the time of fishes reaction and share individuals assigned as bold. Moreover, 21-day recovery lasting might be not enough to get fluoxetine effect on fishes. [ABSTRACT FROM AUTHOR]

Aims: To evaluate the antidepressant‐like effect of compound GW117 in rodents using in vitro binding and uptake assays as well in vivo behavioral tests. Methods: We investigated the target profile of GW117 using [35S]‐GTPγS and [3H]PIP binding. Using the forced swimming test and chronic unpredictable stress in rats, tail suspension test in mice and rats, and learned helplessness model in mice, we further revealed the antidepressant‐like and anxiolytic‐like effects of GW117. Results: The current study suggests that GW117 displays serotonin 2C (5‐HT2C) receptor antagonist and melatonin type 1 and 2 (MT1/MT2) receptor agonist properties, as well as evident antidepressant and anxiolytic effects. Conclusion: These data suggest that GW117 is probably a potent antidepressant. [ABSTRACT FROM AUTHOR]

Aims: The aim of this study was to monitor the trajectories of antidepressant use during pregnancy and the postpartum period among women chronically treated with antidepressants before their pregnancy, and to assess characteristics associated with each trajectory. Methods: This cohort study included all pregnant women whose data were included in the General Sample of Beneficiaries (EGB) database affiliated with the French Health Insurance System, from 2009 to 2014. Women were followed up until 6 months after childbirth. Chronic treatment was defined as exposure over the 6‐month period preceding pregnancy. A group‐based trajectory model (GBMT) was estimated to identify distinctive longitudinal profiles of antidepressant use. Results: Among 760 women chronically treated with antidepressants before their pregnancy, 55.8% stopped their treatment permanently in the first trimester, 20.4% discontinued it for a minimum of 3 months and resumed it postpartum, and 23.8% maintained it throughout pregnancy and postpartum. No sociodemographic or medical characteristics were associated with any trajectory group. Women who maintained treatment presented more frequent obstetric complications and postpartum psychiatric disorders. Among women who interrupted treatment, prescription of benzodiazepines and anxiolytics decreased initially but rose postpartum to a higher level than before pregnancy. Conclusions: Pregnant women treated with antidepressant require a re‐evaluation of psychiatric treatment. It is necessary to pay attention to obstetric complications for severely depressed women. Additionally, as relapse was associated with increased benzodiazepine use, it is important to carefully monitor all women who stop antidepressant treatment during pregnancy. [ABSTRACT FROM AUTHOR]

Piper nigrum L. also called black pepper is popular for its numerous uses. The present research is designed to investigate the pharmacological potential of methanol extract of Piper nigrum (MEPN). The antidepressant investigation was performed by using both in vivo forced swimming test (FST) and tail suspension test (TST) methods while the anxiolytic research by hole‐board test (HBT) method. Again, the antipyretic analysis was conducted through yeast‐induced pyrexia method, whereas clot lysis activity was employed by the thrombolytic method. Furthermore, in silico studies followed by molecular docking analysis of several secondary metabolites, pass prediction, and ADME/T were evaluated with AutoDock Vina, Discovery Studio 2020, UCSF Chimera software PASS online, and ADME/T online tools. The plant extract demonstrated dose‐dependent potentiality in antidepressant, anxiolytic, antipyretic, and thrombolytic activities. Induction of MEPN produced a significant (p <.5, p <.001) increase of mobility in FST and TST, and increased the head dipping and decreased the latency of time (p <.01, p <.001) in HBT. MEPN 400 (mg/kg; b.w.; p.o.) lowered the rectal temperature of yeast‐induced pyrexia substantially (p <.001). Besides, MEPN produced promising (p <.001) clot lysis activity. In the computational approach, among all the proteins, a docking score was found ranging from −1.0 to −7.90 kcal/mol. Besides, all the compounds were found safe in ADME/T study. The results of our scientific research validate the suitability of this plant as an alternative source of novel therapeutics. [ABSTRACT FROM AUTHOR]

Background and Purpose: Arctigenin, a major bioactive component of Fructus arctii, has been reported to have antidepressant-like effects. However, the mechanisms underlying these effects are still unclear. Neuroinflammation can be caused by excessive production of proinflammatory cytokines in microglia via high-mobility group box 1 (HMGB1)/TLR4/NF-κB and TNF-α/TNFR1/NF-κB signalling pathways, leading to depression. In this study, we have investigated the antidepressant mechanism of arctigenin by conducting in vitro and in vivo studies.Experimental Approach: The effects of chronic unpredictable mild stress (CUMS) on wild-type (WT) and TLR4-/- mice were examined. Antidepressant-like effects of arctigenin were tested using the CUMS-induced model of depression in WT mice. The effects of arctigenin were assessed on the HMGB1/TLR4/NF-κB and TNF-α/TNFR1/NF-κB signalling pathways in the prefrontal cortex (PFC) of mouse brain and HMGB1- or TNF-α-stimulated primary cultured microglia. The interaction between HMGB1 and TLR4 or TNF-α and TNFR1 with or without arctigenin was examined by localized surface plasmon resonance (LSPR) and co-immunoprecipitation assays.Key Results: The immobility times in the tail suspension test (TST) and forced swimming test (FST) were reduced in TLR4-/- mice, compared with WT mice. Arctigenin exhibited antidepressant-like effects. Arctigenin also inhibited microglia activation and inflammatory responses in the PFC of mouse brain. Arctigenin inhibited HMGB1 and TLR4 or TNF-α and TNFR1 interactions, and suppressed both HMGB1/TLR4/NF-κB and TNF-α/TNFR1/NF-κB signalling pathways.Conclusions and Implications: Arctigenin has antidepressant-like effects by attenuating excessive microglial activation and neuroinflammation through the HMGB1/TLR4/NF-κB and TNF-α/TNFR1/NF-κB signalling pathways. This suggests that arctigenin has potential as a new drug candidate suitable for clinical trials to treat depression. [ABSTRACT FROM AUTHOR]

Background: Astrocytes have been implicated in the pathophysiology of mood disorders and in the mechanism of the pharmacological effects of antidepressant drugs by the production of neurotrophic/growth factors. Previous studies have identified astrocyte‐expressed Gαi/o‐coupled lysophosphatidic acid receptor 1 (LPAR1), as being involved in antidepressant‐induced production of glial cell line‐derived neurotrophic factor (GDNF) and matrix metalloproteinase‐9 (MMP‐9) activation, an important step in the production of GNDF. However, the precise mechanism of MMP‐9 activation by antidepressants has yet to be identified, in particular the intracellular signaling pathway between LPAR1/Gαi/o and MMP‐9. Methods and Results: Treatment of rat C6 astroglial cells (C6 cells) with amitriptyline increased Src family tyrosine kinase phosphorylation in a time and concentration‐dependent manner. Amitriptyline‐induced GDNF mRNA expression was blocked by Src family tyrosine kinase inhibitors. In addition, inhibiting Src family tyrosine kinase blocked amitriptyline‐induced zymographic MMP‐9 activation in C6 cells. The amitriptyline‐induced zymographic MMP‐9 activity was completely blocked by selective inhibition of Gαi/o protein and LPAR1. Furthermore, the amitriptyline‐induced Src family tyrosine kinase phosphorylation was blocked by LPAR1, but not MMP‐9 inhibition, indicating that Src family tyrosine kinase involvement is downstream of LPAR1. Conclusions: The current findings suggest that the pharmacological effect of antidepressant such as amitriptyline is mediated through an intracellular signaling pathway via the LPAR1/Gαi/o/Src family tyrosine kinase, which leads to MMP‐9 activation and GDNF production. [ABSTRACT FROM AUTHOR]

Aims: Non‐adherence or partial adherence to psychotropic medication is found in 18–70% of patients. Many previously used methods for the assessment of adherence (e.g. questionnaires, pill counts, and electronic systems), however, might underreport actual rates of non‐adherence to medication. The aim of this study was to quantify adherence using plasma level. Methods: We conducted a 6‐week prospective study of all consecutive admitted patients at the Paracelsus Medical University of Salzburg, Clinics of Psychiatry and Psychotherapy, who had been treated with antipsychotics/antidepressants prior to admission (pre‐medication dosage in 161 of 233). Plasma drug levels were determined and compared with expected levels based on known preadmission dosing regimens and average pharmacokinetic data. Results: Seventy‐three percent of the patients had actual plasma levels clearly below or above the intended level. Significantly more patients with schizophrenia (66%) did not take the medication as prescribed, when compared with patients with affective disorders (47%) or those with other psychiatric diagnoses (41%). Only 27% (44 of 161) of the patients had plasma level in the expected range based on the dosage. Conclusion: The risk of partial adherence or non‐adherence is expected in two‐thirds of patients with schizophrenia, half of patients with affective disorders, and approximately 40% of patients with other psychiatric diagnoses. Given that admitting psychiatrists could not provide an accurate assessment of patient adherence, it is strongly suggested that clinical judgment be supplemented with the actual monitoring of adherence – and further optimization of pharmacotherapy – by means of therapeutic drug monitoring. [ABSTRACT FROM AUTHOR]

Nociceptin/Orphanin FQ (N/ OFQ) is a 17 amino acid peptide whose receptor is designated ORL1 or nociceptin receptor ( NOP). We utilized a potent, selective, and orally bioavailable antagonist with documented engagement with NOP receptors in vivo to assess antidepressant- and anxiolytic-related pharmacological effects of NOP receptor blockade along with measures of cognitive and motor impingement. LY2940094 ([2-[4-[(2-chloro-4,4-difluoro-spiro[5H-thieno[2,3-c]pyran-7,4′-piperidine]-1′-yl)methyl]-3-methyl-pyrazol-1-yl]-3-pyridyl]methanol) displayed antidepressant-like behavioral effects in the forced-swim test in mice, an effect absent in NOP−/− mice. LY2940094 also augmented the behavioral effect of fluoxetine without changing target occupancies ( NOP and serotonin reuptake transporter [ SERT]). LY2940094 did not have effects under a differential-reinforcement of low rate schedule. Although anxiolytic-like effects were not observed in some animal models (conditioned suppression, 4-plate test, novelty-suppressed feeding), LY2940094 had effects like that of anxiolytic drugs in three assays: fear-conditioned freezing in mice, stress-induced increases in cerebellar cGMP in mice, and stress-induced hyperthermia in rats. These are the first reports of anxiolytic-like activity with a systemically viable NOP receptor antagonist. LY2940094 did not disrupt performance in either a 5-choice serial reaction time or delayed matching-to-position assay. LY2940094 was also not an activator or suppressor of locomotion in rodents nor did it induce failures of rotarod performance. These data suggest that LY2940094 has unique antidepressant- and anxiolytic-related pharmacological effects in rodents. Clinical proof of concept data on this molecule in depressed patients have been reported elsewhere. [ABSTRACT FROM AUTHOR]

Background and Purpose Phosphodiesterase 4 ( PDE4) inhibitors produce potent antidepressant-like and cognition-enhancing effects. However, their clinical utility is limited by the major side effect of emesis, which appears to be PDE4 isoform-specific. Although PDE4D subtype plays the pivotal role in these therapeutic profiles, it is also the primary subtype responsible for emesis. Therefore, the aim of present research was to investigate whether long-form PDE4D variants mediate antidepressant-like and cognition-enhancing effects, but are irrespective with emesis. Experimental Approach In mice microinfused with lentiviral vectors that contained shRNA-mir hairpin structure targeting long-form PDE4Ds into bilateral prefrontal cortices, the tail-suspension and forced-swim tests were used to measure antidepressant-like effects; novel object recognition and Morris water-maze tasks were used to determine cognition-enhancing effects. The emetic potential was assessed by alpha2 adrenergic receptor-mediated anaesthesia, a surrogate measure of emesis. Intracellular cAMP signalling was analysed by time-resolved FRET immunoassay and Western-blot. Dendritic complexity was assessed by Golgi staining. Key Results Microinfusions of lentiviral PDE4D-shRNA down-regulated PDE4D4 and PDE4D5, and imitated the antidepressant-like and cognition-enhancing effects of the prototypical PDE4 inhibitor rolipram. The behavioural effects were related to dendritic complexity and mediated by the increased cAMP signalling. In addition, these effects were not enhanced in the presence of rolipram. Finally, while rolipram shortened the duration of combined anaesthesia, RNA interference-mediated PDE4D knock-down in the prefrontal cortex did not. Conclusion and Implications These data suggest that long-form PDE4Ds, at least PDE4D4 and PDE4D5, may be the promising targets for the development of PDE4 variant-selective inhibitors as the new pharmacotherapies for depressive disorders and neurodegenerative diseases involving memory deficits. [ABSTRACT FROM AUTHOR]

Antidepressant medication and evidence-based psychotherapy have largely equivalent efficacy in the management of the common, less severe grades of depression. As a result, several national guidelines recommend that either can be used in the treatment of this disorder. Psychotherapy, however, differs in that it assists insight into how the depressed person appraises and manages the stressors that frequently trigger depressive episodes. I argue that the self-knowledge achieved through psychotherapy has moral value in that it promotes the autonomy of stressor-related decisions. I further argue that such an effect comprises a compelling moral reason for doctors to see evidence-based psychotherapy not as merely optional, but as a necessary treatment for their patients with depression. [ABSTRACT FROM AUTHOR]

Background and purpose: As a combination of 5-HT selective reuptake inhibitor (SSRI) with 5-HT1A receptor antagonism may yield a rapidly acting antidepressant, WAY-211612, a compound with both SSRI and 5-HT1A receptor antagonist activities, was evaluated in preclinical models. Experimental approach: Occupancy studies confirmed the mechanism of action of WAY-211612, while its in vivo profile was characterized in microdialysis and behavioural models. Key results: WAY-211612 inhibited 5-HT reuptake (Ki = 1.5 nmol·L−1; KB = 17.7 nmol·L−1) and exhibited full 5-HT1A receptor antagonist activity (Ki = 1.2 nmol·L−1; KB = 6.3 nmol·L−1; Imax 100% in adenyl cyclase assays; KB = 19.8 nmol·L−1; Imax 100% in GTPγS). WAY-211612 (3 and 30 mg·kg−1, po) occupied 5-HT reuptake sites in rat prefrontal cortex (56.6% and 73.6% respectively) and hippocampus (52.2% and 78.5%), and 5-HT1A receptors in the prefrontal cortex (6.7% and 44.7%), hippocampus (8.3% and 48.6%) and dorsal raphe (15% and 83%). Acute or chronic treatment with WAY-211612 (3–30 mg·kg−1, po) raised levels of cortical 5-HT approximately twofold, as also observed with a combination of an SSRI (fluoxetine; 30 mg·kg−1, s.c.) and a 5-HT1A antagonist (WAY-100635; 0.3 mg·kg−1, s.c). WAY-211612 (3.3–30 mg·kg−1, s.c.) decreased aggressive behaviour in the resident-intruder model, while increasing the number of punished crossings (3–30 mg·kg−1, i.p. and 10–56 mg·kg−1, po) in the mouse four-plate model and decreased adjunctive drinking behaviour (56 mg·kg−1, i.p.) in the rat scheduled-induced polydipsia model. Conclusions and implications: These findings suggest that WAY-211612 may represent a novel antidepressant. [ABSTRACT FROM AUTHOR]

Background and purpose: Activation of post-synaptic 5-HT1A receptors may provide enhanced therapy against depression. We describe the signal transduction profile of F15599, a novel 5-HT1A receptor agonist. Experimental approach: F15599 was compared with a chemical congener, F13714, and with (+)8-OH-DPAT in models of signal transduction in vitro and ex vivo. Key results: F15599 was highly selective for 5-HT1A receptors in binding experiments and in [35S]-GTPγS autoradiography of rat brain, where F15599 increased labelling in regions expressing 5-HT1A receptors. In cell lines expressing h5-HT1A receptors, F15599 more potently stimulated extracellular signal-regulated kinase (ERK1/2) phosphorylation, compared with G-protein activation, internalization of h5-HT1A receptors or inhibition of cAMP accumulation. F13714, (+)8-OH-DPAT and 5-HT displayed a different rank order of potency for these responses. F15599 stimulated [35S]-GTPγS binding more potently in frontal cortex than raphe. F15599, unlike 5-HT, more potently and efficaciously stimulated Gαi than Gαo activation. In rat prefrontal cortex (a region expressing post-synaptic 5-HT1A receptors), F15599 potently activated ERK1/2 phosphorylation and strongly induced c-fos mRNA expression. In contrast, in raphe regions (expressing pre-synaptic 5-HT1A receptors) F15599 only weakly or did not induce c-fos mRNA expression. Finally, despite its more modest affinity in vitro, F15599 bound to 5-HT1A receptors in vivo almost as potently as F13714. Conclusions and implications: F15599 showed a distinctive activation profiles for 5-HT1A receptor-mediated signalling pathways, unlike those of reference agonists and consistent with functional selectivity at 5-HT1A receptors. In rat, F15599 potently activated signalling in prefrontal cortex, a feature likely to underlie its beneficial effects in models of depression and cognition. Mandarin translation of abstract [ABSTRACT FROM AUTHOR]

1 Incubation of LMCAT fibroblast cells with antidepressants potentiates glucocorticoid receptor (GR)-mediated gene transcription in the presence of dexarnethasone and cortisol, but not of corticosterone. We have shown that antidepressants do so by inhibiting the LMCAT cell membrane steroid transporter (which is virtually identical to the multidrug resistance P-glycoprotein) and thus by increasing dexamethasone or cortisol intracellular concentrations. However, previous experiments with the antidepressant Iluoxetine in the presence of dexamethasone have produced negative results (Pariante et al. (2001). Br. J. Pharmacol., 134, l335-l343). 2 We have since re-examined the effects of fluoxetine on GR-mediated gene transcription in the presence of dexamethasone. Moreover, we have examined the effects of fluoxetine on GR-mediated gene transcription in the presence of cortisol and corticosterone, and on the intracellular accumulation of radioactive cortisol and corticosterone. Finally, we have examined the effects of fluoxetine on inhibition of P-giyeoprotein activity in Caco-2 cells. 3 We now find that fluoxetine (1 - 10μM) enhances GR-mediated gene transcription in the presence of dexanlethasone and cortisoi (+140-170%), but not of corticosterone, and increases the intracellular accumulation of 3H-eortisol (+ 5-15%), but not of 3H-corticosterone. Moreover, fluoxetine (10 μM) induces approximately 30% inhibition of PGP activity in Caco-2 cells. 4 Our results show that fluoxetine, like other antidepressants, inhibits membrane steroid transporters. [ABSTRACT FROM AUTHOR]

Selecting the most effective antidepressant for depressed subjects having failed previous treatments is difficult; the rates of success are relatively low. There is a clear need for objective biomarkers which could assist and optimize such treatment selection. We review here the current literature and recent developments on the role of quantitative EEG (QEEG) predictors of treatment outcome in major depressive disorder. [ABSTRACT FROM AUTHOR]

Clinical psychopharmacological research has focused on several aspects in the last decade in China. First, attention was paid to new drug trials, mainly on newly developed or imported antidepressants or antipsychotics. More and more newly developed antidepressants like SSRI, fluoxetine, paroxetine, sertraline, and citalopram are now available or under clinical observation. Second, studies on the relationship between blood level and clinical response of antidepressants, amitriptyline, or antipsychotics, haloperidol and clozapine were undertaken. Results on amitriptyline showed that the clinical antidepressive effect of the drug was correlated linearly to the parent compound, amitriptyline, and curvilinearly to the hydroxylated metabolite, 10-hydroxynortryptyline. It was found that the plasma level of haloperidol correlated curvilinearly to the clinical antipsychotic effect on schizophrenics with a therapeutic window ranging between 4.2 and 20 ng/mL. Third, pharmacokinetic studies on antidepressants, amitriptyline, imipramine, and maprotiline were undertaken. The results showed longer clearance rate and/or t1/2 in Chinese literature than those reported in Western literature. [ABSTRACT FROM AUTHOR]