piperidines and Depressive-Disorder--Major

Major depressive disorder (MDD) is widely prevalent and one of the leading causes of disability. Treatment outcomes remain suboptimal with 1 in 3 patients with MDD responding inadequately to commonly used antidepressants. Pimavanserin, an atypical antipsychotic that modulates serotonergic neurotransmission by selectively binding to serotonin receptor (2A and 2C) subtypes and without dopaminergic activity, may have the potential as an adjunctive treatment for MDD. In a phase 2 trial (n=203), addition of pimavanserin, as compared to placebo, to stable treatment with antidepressants was associated with greater reduction in 17-item Hamilton Depression Rating Scale score [HAMD, least square means (95% confidence interval) of -1.7 (-0.03, -3.37), p=0.039]. Furthermore, treatment with pimavanserin was associated with significantly greater improvement in specific symptoms associated with depression such as impaired sexual function, anxiety, sleepiness, and irritability. However, the availability of pimavanserin for clinical care of patients with MDD remains uncertain. Top-line results of phase 3 studies (n=298) that were announced by the sponsor found similar reductions in HAMD (mean baseline-to-week-5 reduction of 9.0 and 8.1, p=0.296) and rates of adverse events (58.1% and 54.7%) with addition of pimavanserin and placebo respectively to stable treatment with antidepressants. Given the potential benefit for specific symptoms such as impaired sexual function, anxiety and sleep/wakefulness disturbances, future studies that enrich for these symptoms may be needed to clarify the utility of adjunctive pimavanserin in treatment of patients with MDD.

Topics: Antipsychotic Agents; Depressive Disorder, Major; Humans; Piperidines; Receptors, Serotonin; Urea

Major depression is a frequent psychiatric disease. One- third of the depressive patients remain treatment-resistant; thus, it is urgent to find novel antidepressant drugs.. In major depression, in several brain areas the neural networks involved and the alterations of neurotransmitters and neuropeptides are updated. According to these networks, new pharmacological agents and effective combinations of antidepressant drugs achieving a more efficacious antidepressant treatment are suggested.. In the neural networks, the prefrontal cortex has been included. In this brain area, glutamatergic neurons, which receive an activating potential from D2 dopaminergic neurons, presynaptically inhibit M1 muscarinic cholinergic neurons via NMDA receptors. Medium spiny GABAergic/somatostatin neurons, which receive projections from M1 muscarinic cholinergic neurons, presynaptically inhibit D2 dopaminergic neurons via GABAA/somatostatin1 receptors. The combination of an NMDA receptor antagonist with an M1 muscarinic cholinergic receptor antagonist can achive a rapid, long-lasting antidepressant effect.. In preclinical studies, the antidepressant effect of orvepitant, an NK1 receptor antagonist, has been demonstrated: this antagonist reaches a complete blockade of NK1 receptors. In clinical studies, the combination of an NMDA receptor antagonist with an M1 muscarinic cholinergic receptor antagonist should be investigated indepth as well as the therapeutic effect of orvepitant. In clinical studies, the antidepressant effect of a triple reuptake inhibitor should be examined and compared to current antidepressant drugs.

Topics: Acetamides; Animals; Antidepressive Agents; Bridged Bicyclo Compounds, Heterocyclic; Depressive Disorder, Major; Humans; Muscarinic Antagonists; Neuropeptides; Neurotransmitter Agents; Piperidines; Receptors, N-Methyl-D-Aspartate

Positive allosteric modulation of mGlu2 has attracted much interest as an alternative approach to classical orthosteric receptor activation. Two mGlu2 PAMS have advanced into the clinic. The results obtained in schizophrenia and MDD phase 2 clinical trials have tempered the high expectations put on selective mGlu2 receptor activation for treating these conditions; nevertheless, the search for novel therapeutic indications and novel chemotypes continues to be an active field of research.. 2013-2018 patent literature on mGlu2 receptor PAMs.. After a decade of intensive research, the mGlu2 PAM field has seen a deceleration in the last five years. Negative phase 2 schizophrenia clinical trials with JNJ-40411813 and AZD8529 seem to have tempered the high expectations of the scientific community on the utility of mGlu2 PAMs for the treatment of schizophrenia. Nevertheless, novel therapeutic indications continue to be explored and AZD8529 is currently in a phase 2 study for smoking cessation. The advances in medicinal chemistry and in pharmacology, with novel indications such as epilepsy, have set the stage in the field of mGlu2 receptor PAMs. Ongoing preclinical and clinical studies will contribute to define their optimal therapeutic indication and potential to become novel therapeutic agents.

Topics: Allosteric Regulation; Animals; Depressive Disorder, Major; Humans; Indoles; Oxadiazoles; Patents as Topic; Piperidines; Pyridones; Receptors, Metabotropic Glutamate; Schizophrenia

The difference in location between the receptor occupancy curve of an agonist and its functional response has been described as receptor reserve. This "reserve" for a specific receptor has been found to differ from tissue to tissue and between agonists acting on the same tissue. Recently, two structurally different neurokinin 1 (NK1) receptor antagonists were taken into human and both were tested as antidepressants and for insomnia. Vestipitant and Casopitant both have high affinity for the human NK1 receptor (pKi = 9.4 and 10.2, respectively). In human, at the chosen clinical doses, receptor occupancy was measured in the frontal cortex, at 24 hours post administration, as ∼90% for vestipitant (15 mg) and ∼100% for casopitant (30 mg). In patients with moderate to severe major depression, vestipitant given at 15 mg for 8 weeks showed no statistical significant benefit as measured by change in baseline in HAM-D total score; whereas casopitant at 80 mg achieved statistically significant improvement versus placebo at week 8 (LOCF HAMD17 = -2.7, p = 0.023). A lower dose of 30 mg showed a clear but not significant separation from placebo. However, in acute studies in insomnia, both vestipitant and casopitant at 15 mg and 30 mg, respectively, significantly reduced latency to persistent sleep, wakenings after sleep onset and increased total sleep time by similar amounts. These clinical results suggest that for major depression the receptor occupancy of an NK1 antagonist needs to be very high (almost 100%), whereas, for insomnia a lower occupation is sufficient to give clinical effect.

Topics: Antidepressive Agents; Depressive Disorder, Major; Fluorobenzenes; Humans; Neurokinin-1 Receptor Antagonists; Piperazines; Piperidines; Receptors, Neurokinin-1; Sleep Initiation and Maintenance Disorders; Tissue Distribution

Several treatment strategies for augmenting outcomes with ECT (concurrent antidepressant treatment, frequency of ECT treatments, hyperventilation and use of remifentanil) are discussed in the context of a difficult clinical case, accompanied by a review of the relevant existing literature.. Literature on the above aspects of ECT technique was identified via a PubMed search and was critically reviewed.. There is preliminary evidence that concurrent administration of some antidepressant medications may be useful in the highly treatment resistant patient, though due attention should be given to potential risks in combining these with ECT; reduction of the treatment frequency to twice a week; hyperventilation prior to each treatment; and the use of remifentanil to minimise the dosage of induction anaesthetics with anticonvulsant properties, may be useful strategies to enhance seizure production in cases where a high or rapidly rising seizure threshold is a major impediment to ECT treatment.. It should be noted that empirical evidence for the effectiveness of each of the above strategies in producing better outcomes with ECT is not definitive, pointing to the need for further research in these areas.. The above strategies may be useful in clinical ECT practice, particularly in patients who are apparently treatment resistant, but the practitioner should be aware that the level of evidence underpinning these approaches is at present, preliminary.

Topics: Aged; Anesthesia, General; Anesthetics, Intravenous; Anticonvulsants; Antidepressive Agents; Contraindications; Depressive Disorder, Major; Dominance, Cerebral; Dose-Response Relationship, Drug; Drug Interactions; Drug Therapy, Combination; Electroconvulsive Therapy; Electroencephalography; Female; Frontal Lobe; Humans; Hyperventilation; Mental Status Schedule; Piperidines; Recurrence; Remifentanil; Retreatment; Suicide, Attempted; Temporal Lobe

Saredutant (SR48968), a potentially novel treatment option for major depressive disorders (MDD) and generalized anxiety disorder (GAD), is a drug from Sanofi-Aventis currently in phase III clinical trials. MDD is a common mental disorder that affects 121 million people worldwide, nearly 4% of the adult population (www.who.int/mental_health/management/depression/definition/en/). MDD continues to be one of the leading causes of disability with more than three quarters of the diagnosed cases having effective treatments available (www.who.int/mental_health/management/depression/definition/en/). However, even though MDD affects a large portion of the population, effective treatment options with low incidence of adverse events remain a major concern for the pharmaceutical industry. Adverse events (GI side effects1, weight gain, somnolence/insomnia, etc. (Demyttenaere K. (2003) Risk factors and predictors of compliance in depressionEur. Neuropshychopharm.13S69-S75)) from the typical treatments remain the major reason for premature stopping or poor compliance of treatment. New treatments to the market must bear in mind these adverse events, and the pharmaceutical industry is currently looking for drugs with new mechanisms of action and those that are better tolerated.

Topics: Antidepressive Agents; Anxiety Disorders; Benzamides; Clinical Trials, Phase III as Topic; Depressive Disorder, Major; Humans; Neurokinin A; Patient Compliance; Piperidines; Psychiatric Status Rating Scales; Selective Serotonin Reuptake Inhibitors

N-methyl-D-aspartate receptors (NMDARs) are ion channels gated by glutamate, the major excitatory neurotransmitter in the mammalian central nervous system (CNS). They are widespread in the CNS and are involved in numerous physiological and pathological processes including synaptic plasticity, chronic pain and psychosis. Aberrant NMDAR activity also plays an important role in the neuronal loss associated with ischaemic insults and major degenerative disorders including Parkinson's and Alzheimer's disease. Agents that target and alter NMDAR function may, thus, have therapeutic benefit. Interestingly, NMDARs are endowed with multiple extracellular regulatory sites that recognize ions or small molecule ligands, some of which are likely to regulate receptor function in vivo. These allosteric sites, which differ from agonist-binding and channel-permeation sites, provide means to modulate, either positively or negatively, NMDAR activity. The present review focuses on allosteric modulation of NMDARs containing the NR2B subunit. Indeed, the NR2B subunit confers a particularly rich pharmacology with distinct recognition sites for exogenous and endogenous allosteric ligands. Moreover, NR2B-containing receptors, compared with other NMDAR subtypes, appear to contribute preferentially to pathological processes linked to overexcitation of glutamatergic pathways. The actions of extracellular H+, Mg2+, Zn2+, of polyamines and neurosteroids, and of the synthetic compounds ifenprodil and derivatives ('prodils') are presented. Particular emphasis is put upon the structural determinants and molecular mechanisms that underlie the effects exerted by these agents. A better understanding of how NR2B-containing NMDARs (and NMDARs in general) operate and how they can be modulated should help define new strategies to counteract the deleterious effects of dysregulated NMDAR activity.

Topics: Allosteric Regulation; Allosteric Site; Animals; Brain Diseases; Depressive Disorder, Major; Humans; Magnesium; Neurotransmitter Agents; Pain; Piperidines; Polyamines; Protein Subunits; Receptors, N-Methyl-D-Aspartate; Synaptic Transmission; Zinc

Casopitant, an inhibitor of the neurokinin-1 receptor, and its mesylate salt, are being developed by GlaxoSmithKline plc for the potential treatment of chemotherapy-induced nausea and vomiting (CINV), post-operative nausea and vomiting (PONV), as well as for anxiety, depression and insomnia. Phase II trials are ongoing for anxiety, depression and insomnia, and further results are awaited from phase III trials of CINV and PONV. At the time of publication, it was expected that applications to the FDA for regulatory approval for CINV and PONV would be filed in 2008. Casopitant was previously being developed for the treatment of overactive bladder; however, in September 2007, this indication was no longer listed on the company's product pipeline.

Topics: Animals; Antiemetics; Anxiety Disorders; Clinical Trials as Topic; Contraindications; Depressive Disorder, Major; Drug Evaluation, Preclinical; Female; Fibromyalgia; Humans; Nausea; Neurokinin-1 Receptor Antagonists; Patents as Topic; Piperazines; Piperidines; Postoperative Nausea and Vomiting; Structure-Activity Relationship; Urinary Bladder, Overactive; Vomiting

It has been long known that the frequency of overweight and obese people is higher among depressed and bipolar patients than in the general population. The marked alteration of body weight (and appetite) is one of the most frequent of the 9 symptoms of major depressive episode, and these symptoms occur during recurrent episodes of depression with a remarkably high consequence. According to studies with representative adult population samples, in case of obesity (BMI over 30) unipolar or bipolar depression is significantly more frequently (20-45%) observable. Since in case of depressed patients appetite and body weight reduction is observable during the acute phase, the more frequent obesity in case of depressed patients is related (primarily) not only to depressive episodes, but rather to lifestyle factors, to diabetes mellitus also more frequently occurring in depressed patients, to comorbid bulimia, and probably to genetic-biological factors (as well as to pharmacotherapy in case of medicated patients). At the same time, according to certain studies, circadian symptoms of depression give rise to such metabolic processes in the body which eventually lead to obesity and insulin resistance. According to studies in unipolar and bipolar patients, 57-68% of patients is overweight or obese, and the rate of metabolic syndrome was found to be between 25-49% in bipolar patients. The rate of metabolic syndrome is further increased by pharmacotherapy. Low total and HDL cholesterol level increases the risk for depression and suicide and recent studies suggest that omega-3-fatty acids possess antidepressive efficacy. Certain lifestyle factors relevant to healthy metabolism (calorie reduction in food intake, regular exercise) may be protective factors related to depression as well. The depression- and possibly suicide-provoking effect of sibutramine and rimonabant used in the pharmacotherapy of obesity is one of the greatest recent challenges for professionals and patients alike.

Topics: Anti-Obesity Agents; Antidepressive Agents; Appetite Depressants; Appetite Regulation; Bipolar Disorder; Circadian Rhythm; Cyclobutanes; Depression; Depressive Disorder, Major; Dietary Carbohydrates; Energy Intake; Ghrelin; Humans; Hypothalamo-Hypophyseal System; Insulin Resistance; Leptin; Obesity; Piperidines; Pituitary-Adrenal System; Pyrazoles; Rimonabant; Seasonal Affective Disorder; Sleep Wake Disorders; Surveys and Questionnaires; Weight Gain; Weight Loss

Tipepidine, a synthetic, non-opioid expectorant, has been shown to improve depressive-like behavior in animal models of depression. In this study, we assessed the efficacy and tolerability of tipepidine combination therapy with citalopram in treatment of major depressive disorder (MDD).. In a randomized, double-blinded, placebo-controlled clinical trial, 62 patients with MDD were assigned into two parallel groups to receive citalopram (up to 40 mg/day) plus placebo or citalopram plus tipepidine (30 mg twice daily) for 6 weeks. Participants were assessed with the Hamilton Rating Scale for Depression (HAM-D) at baseline and Weeks 2, 4, and 6.. Fifty-six patients completed the trial. The tipepidine group showed greater improvement in HAM-D scores from baseline to all three study time points (P = 0.048 for all). The remission and response-to-treatment rates were significantly higher in the tipepidine group (53.6% and 100%) compared to the placebo group (25.0% and 75%) at the study end-point (P = 0.029 and 0.005, respectively). The remission and response times in patients in the tipepidine group were also shorter compared with the placebo group (log-rank P = 0.020 and 0.004). There was no significant difference between the two groups in baseline parameters or frequency of side-effects.. Tipepidine combination therapy with citalopram can effectively improve symptoms of patients with MDD in a shorter period of treatment. However, further studies with larger sample sizes and longer follow-up treatment are needed to confirm our findings.

Topics: Adult; Citalopram; Depressive Disorder, Major; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Outcome Assessment, Health Care; Piperidines; Selective Serotonin Reuptake Inhibitors; Time Factors

In a post hoc analysis, the effect of pimavanserin on anxious depression was determined from CLARITY, a randomized, double-blind, placebo-controlled study in patients with major depression and an inadequate response to previous therapy. Patients were randomized in a 3:1 ratio to placebo or pimavanserin 34 mg daily added to ongoing antidepressant therapy. At 5 weeks, placebo nonresponders were rerandomized to placebo or pimavanserin for an additional 5 weeks. Mean change from baseline to week 5 for the Hamilton depression rating scale (HAMD) anxiety/somatization (AS) factor was examined for all patients and those with a score ≥7 at baseline. Least squares (LS) mean [standard error (SE)] difference between placebo and pimavanserin for the AS factor score was -1.5 (0.41) [95% confidence interval (CI) -2.4 to -0.7; P = 0.0003; effect size: 0.634]. Among patients with an AS factor score ≥7 at baseline, LS mean (SE) difference was -2.2 (0.66) (95% CI -3.5 to -0.9; P = 0.0013; effect size: 0.781). Response rates (≥50% reduction in HAMD-17 from baseline) were 22.4 and 55.2% (P = 0.0012) and remission rates (HAMD-17 total score <7) were 5.3 and 24.1% (P = 0.0047), respectively, with placebo and pimavanserin among patients with a baseline AS factor score ≥7. Among patients with anxious major depressive disorder at baseline, adjunctive pimavanserin was associated with a significant improvement.

Topics: Adult; Antidepressive Agents; Antipsychotic Agents; Anxiety; Depression; Depressive Disorder, Major; Double-Blind Method; Female; Humans; Male; Middle Aged; Piperidines; Urea

Up to 15% of patients with major depressive disorder (MDD) attempt suicide and up to 2% complete suicide. This was a post-hoc analysis aimed to evaluate the risk of suicide ideation and behavior associated with adjunctive pimavanserin treatment in adults with MDD.. CLARITY was a randomized, double-blind, placebo-controlled study in patients with MDD and an inadequate response to a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI). For this post-hoc analysis, the primary endpoint was mean change from baseline for HAMD item 3 (suicide). The incidence of suicidal ideation or behavior was also assessed from the Columbia-Suicide Severity Rating Scale (C-SSRS) and reports of adverse events.. During Stage 1, LS mean change for HAMD Item 3 was reduced from baseline at each week with pimavanserin with a significant difference between pimavanserin and placebo at Week 3 (p=0.012, effect size: 0.431). At any post-baseline assessment, suicidal ideation on the C-SSRS was reported in 28 (18.1%) of patients with placebo and 9 (17.3%) with pimavanserin during Stage 1 and in 7 (20.7%) with placebo and 4 (13.8%) with pimavanserin during Stage 2. No events of suicidal behavior were observed with either placebo or pimavanserin.. The post hoc nature, exclusion of patients with any history of suicide from the primary study, and the small number of patients who demonstrated evidence of suicidal ideation.. Adjunctive pimavanserin was not associated with an increase in suicidal ideation in patients with MDD. Further study is needed to verify these results.

Topics: Adult; Depression; Depressive Disorder, Major; Double-Blind Method; Humans; Piperidines; Suicidal Ideation; Urea

This was an analysis of the effect of pimavanserin, a 5-hydroxytryptamine-2A antagonist and inverse receptor agonist, on dysregulated sleep in patients with major depressive disorder (MDD) by DSM-5 criteria and an inadequate antidepressant response.. For this analysis of CLARITY, a phase 2 study of adjunctive pimavanserin (N = 207) conducted between December 2016 and October 2018, sleep/wakefulness disturbances were measured with the 17-item Hamilton Depression Rating Scale (HDRS₁₇) insomnia items (sum of items 4, 5, and 6) and the Karolinska Sleepiness Scale (KSS). Outcomes included change from baseline in HDRS₁₇ insomnia factor score and KSS score, correlation between the HDRS₁₇ insomnia factor score and KSS score, and change from baseline in the Sheehan Disability Scale (SDS) total score and Unproductive Days subscore in patients with a baseline KSS score ≥ 6.. At baseline, HDRS₁₇ insomnia factor score ≥ 3 occurred in 76% of patients receiving placebo and 85% of patients receiving pimavanserin. The overall least squares (LS) mean weighted difference (SE) was -0.5 (0.32) with a 95% CI of -1.2 to 0.1 (P = .088) at week 5. Improvement was observed with pimavanserin versus placebo at weeks 2, 3, and 4, with effect sizes (ESs) of 0.370 to 0.524 (P < .05). For KSS score, the LS mean difference (SE) at week 5 was -1.1 (0.30) (95% CI, -1.7 to -0.5; P = .0003; ES = 0.627) for pimavanserin versus placebo. Among those with a KSS score ≥ 6 at baseline (n = 120 placebo and n = 42 pimavanserin), the LS mean difference (SE) in the mean SDS score at week 5 was -1.1 (0.46) (95% CI, -2.0 to -0.2; P = .019; ES = 0.442) for pimavanserin versus placebo.. Adjunctive pimavanserin significantly improved sleep/wakefulness disturbance during treatment of MDD, an improvement that was associated with greater improvement in function.. ClinicalTrials.gov identifier: NCT03018340.

Topics: Adolescent; Adult; Aged; Antidepressive Agents; Depressive Disorder, Major; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Linear Models; Male; Middle Aged; Piperidines; Serotonin 5-HT2 Receptor Antagonists; Sleep Wake Disorders; Treatment Outcome; Urea; Young Adult

Pimavanserin is a 5-hydroxytryptamine-2A antagonist and inverse receptor agonist. This phase 2 study examined the efficacy and safety of pimavanserin as adjunctive therapy in patients with major depressive disorder (MDD).. This was a multicenter, randomized, double-blind, placebo-controlled study in patients with DSM-5-defined MDD and an inadequate response to a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI). Using a 2-stage sequential parallel-comparison design, patients were initially randomized in a 3:1 ratio to placebo or pimavanserin added to ongoing SSRI or SNRI therapy; at 5 weeks, placebo nonresponders were re-randomized to placebo or pimavanserin for an additional 5 weeks. Key endpoints were change from baseline to the end of each stage in 17-item Hamilton Depression Rating Scale (HDRS-17) total score and Sheehan Disability Scale (SDS) score.. Between December 2016 and October 2018, 207 patients were randomized. For the prespecified pooled Sequential Parallel Comparison Design analyses of Stages 1 and 2, the least squares (LS) mean (SE) difference for the HDRS-17 total score was -1.7 (0.85) (P = .039) and for the SDS score was -0.8 (0.29) (P = .004). At week 5 of Stage 1, LS mean (SE) difference for pimavanserin versus placebo was significant for changes on the HDRS-17 (-4.0 [1.09], P = .0003) and SDS (-1.2 [0.40], P = .0036) with effect sizes of 0.626 and 0.498, respectively. Early and sustained separation of pimavanserin from placebo (P < .05) occurred at 1 week. The most common adverse events with pimavanserin were dry mouth, nausea, and headache.. Pimavanserin demonstrated robust efficacy in patients with MDD and an inadequate response to an SSRI or SNRI. Tolerability was consistent with previous experience.. ClinicalTrials.gov identifier: NCT03018340.

Topics: Adult; Aged; Depressive Disorder, Major; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Piperidines; Selective Serotonin Reuptake Inhibitors; Treatment Outcome; Urea; Young Adult

We evaluated the effects of a single loading dose of remifentanil (1 μg/kg) administered as an adjunct to sevoflurane, on the duration of seizure activity, recovery times, and hemodynamic profiles, during electroconvulsive therapy.. The patients were randomly allocated to receive sevoflurane-saline (Group SS) or sevoflurane-remifentanil (Group SR). Sevoflurane (8%) was initiated for anesthesia induction in both groups until loss of consciousness was achieved. Remifentanil was then administered to Group SR via a 1-μg/kg intravenous bolus. Patients in Group SS received saline in the same manner. Mean arterial pressure (MAP) and heart rate (HR) were recorded before anesthetic induction (T1), at the loss of consciousness (T2), and at 0, 1, 3, and 10 minutes after the electrical stimuli were completed (T3, T4, T5, and T6, respectively).. Compared with the baseline values, HR increased significantly in Group SS at times T2 and T4 to T6 and decreased significantly in Group SR at time T2. When the groups were compared, we found that HR decreased significantly in Group SR at T2 and T4 to T6. Compared with baseline, MAP increased in Group SS between T3 and T6, and MAP decreased in Group SR at T2 and increased at T3 to T4. Mean arterial pressure decreased to a greater extent in Group SR than in Group SS during the T2 to T6 period. There were no group differences in seizure duration or recovery time.. The addition of 1-μg/kg remifentanil to anesthetic induction with sevoflurane attenuated the acute hemodynamic response to electroconvulsive therapy under sevoflurane anesthesia without adversely affecting the duration of seizure activity or the recovery profile.

Topics: Adult; Anesthesia; Anesthesia Recovery Period; Anesthetics, Inhalation; Anesthetics, Intravenous; Arterial Pressure; Depressive Disorder, Major; Electroconvulsive Therapy; Female; Heart Rate; Hemodynamics; Humans; Male; Methyl Ethers; Oxygen; Piperidines; Remifentanil; Sevoflurane

We evaluated the orexin receptor antagonist filorexant (MK-6096) for treatment augmentation in patients with major depressive disorder.. We conducted a 6-week, double-blind, placebo-controlled, parallel-group, Phase II, proof-of-concept study. Patients with major depressive disorder (partial responders to ongoing antidepressant therapy) were randomized 1:1 to once-daily oral filorexant 10 mg or matching placebo.. Due to enrollment challenges, the study was terminated early, resulting in insufficient statistical power to detect a prespecified treatment difference; of 326 patients planned, 129 (40%) were randomized and 128 took treatment. There was no statistically significant difference in the primary endpoint of change from baseline to week 6 in Montgomery Asberg Depression Rating Scale total score; the estimated treatment difference for filorexant-placebo was -0.7 (with negative values favoring filorexant) (P=.679). The most common adverse events were somnolence and suicidal ideation.. The interpretation of the results is limited by the enrollment, which was less than originally planned, but the available data do not suggest efficacy of orexin receptor antagonism with filorexant for the treatment of depression. (Clinical Trial Registry: clinicaltrials.gov: NCT01554176).

Topics: Adult; Antidepressive Agents; Depressive Disorder, Major; Double-Blind Method; Female; Humans; Male; Middle Aged; Orexin Receptor Antagonists; Piperidines; Proof of Concept Study; Pyrimidines; Treatment Failure; Young Adult

Current medications have limited efficacy in controlling the symptoms of major depressive disorder (MDD), and are associated with several adverse events on long-term use. Curcuminoids are extremely safe and multifunctional phytopharmaceuticals that have been shown to alleviate depressive symptoms in a variety of experimental models. The present study aimed to investigate the efficacy of curcuminoids as an add-on to standard antidepressants in patients with MDD. One hundred and eleven subjects were assigned to standard antidepressive therapy plus curcuminoids-piperine combination (1000-10 mg/day; n=61) or standard antidepressive therapy alone (n=50) for a period of 6 weeks. Efficacy measures were changes in the psychological status on the basis of the Hospital Anxiety and Depression Scale (HADS) and Beck Depression Inventory II (BDI-II). The BDI-II and HADS total and subscale scores were reduced by the end of trial in both study groups. There were significantly greater reductions in total HADS score and subscales of anxiety and depression in the curcuminoids versus control group (p<0.001). Likewise, reductions in BDI-II total score and scores of somatic and cognitive subscales were found to be greater in the curcuminoids compared with control group (p<0.001). Co-administration of curcuminoids with piperine may be used as a safe and effective add-on to standard antidepressants in patients with MDD.

Topics: Adult; Alkaloids; Antidepressive Agents; Anxiety; Benzodioxoles; Biological Availability; Curcumin; Depressive Disorder, Major; Female; Humans; Male; Middle Aged; Piperidines; Polyunsaturated Alkamides; Psychiatric Status Rating Scales

Full, persistent blockade of central neurokinin-1 (NK1) receptors may be a potential antidepressant mechanism. The selective NK1 antagonist orvepitant (GW823296) was used to test this hypothesis. A preliminary positron emission tomography study in eight male volunteers drove dose selection for two randomized six week studies in patients with major depressive disorder (MDD). Displacement of central [(11)C]GR205171 binding indicated that oral orvepitant doses of 30-60 mg/day provided >99% receptor occupancy for ≥24 h. Studies 733 and 833 randomized patients with MDD and 17-item Hamilton Depression Rating Scale (HAM-D)≥22 to double-blind treatment with orvepitant 30 mg/day, orvepitant 60 mg/day or placebo (1:1:1). Primary outcome measure was change from baseline in 17-item HAM-D total score at Week 6 analyzed using mixed models repeated measures. Study 733 (n=328) demonstrated efficacy on the primary endpoint (estimated drug-placebo differences of 30 mg: -2.41, 95% confidence interval (CI) (-4.50 to -0.31) p=0.0245; 60 mg: -2.86, 95% CI (-4.97 to -0.75) p=0.0082). Study 833 (n=345) did not show significance (estimated drug-placebo differences of 30 mg: -1.67, 95% CI (-3.73 to 0.39) p=0.1122; 60 mg: -0.76, 95% CI (-2.85 to 1.32) p=0.4713). The results support the hypothesis that full, long lasting blockade of central NK1 receptors may be an efficacious mechanism for the treatment of MDD.

Topics: Adult; Aged; Antidepressive Agents; Bridged Bicyclo Compounds, Heterocyclic; Depressive Disorder, Major; Double-Blind Method; Humans; Male; Middle Aged; Neurokinin-1 Receptor Antagonists; Piperidines; Positron-Emission Tomography; Radioligand Assay

Cognitive impairment in late-life depression is a core feature of the illness.. To test whether donepezil hydrochloride and antidepressant therapy is superior to placebo and antidepressant therapy in improving cognitive performance and instrumental activities of daily living and in reducing recurrences of depression over 2 years of maintenance treatment.. Randomized, double-blind, placebo-controlled maintenance trial.. University clinic.. One hundred thirty older adults aged 65 years and older with recently remitted major depression.. Random assignment to maintenance antidepressant pharmacotherapy and donepezil or to maintenance antidepressant pharmacotherapy and placebo.. Global neuropsychological performance, cognitive instrumental activities of daily living, and recurrent depression.. Donepezil and antidepressant therapy temporarily improved global cognition (treatment × time interaction, F₂,₂₁₆ = 3.78; P = .03), but effect sizes were small (Cohen d = 0.27, group difference at 1 year). A marginal benefit to cognitive instrumental activities of daily living was also observed (treatment × time interaction, F₂,₁₃₇ = 2.94; P = .06). The donepezil group was more likely than the placebo group to experience recurrent major depression (35% [95% confidence interval {CI}, 24%-46%] vs 19% [95% CI, 9%-29%], respectively; log-rank χ² = 3.97; P = .05; hazard ratio = 2.09 [95% CI, 1.00-4.41]). Post hoc subgroup analyses showed that of 57 participants with mild cognitive impairment, 3 of 30 participants (10% [95% CI, 0%-21%]) receiving donepezil and 9 of 27 participants (33% [95% CI, 16%-51%]) receiving placebo had a conversion to dementia over 2 years (Fisher exact test, P = .05). The mild cognitive impairment subgroup had recurrence rates of major depression of 44% with donepezil vs 12% with placebo (likelihood ratio = 4.91; P = .03). The subgroup with normal cognition (n = 73) showed no benefit with donepezil and no increase in recurrence of major depression.. Whether a cholinesterase inhibitor should be used as augmentation in the maintenance treatment of late-life depression depends on a careful weighing of risks and benefits in those with mild cognitive impairment. In cognitively intact patients, donepezil appears to have no clear benefit for preventing progression to mild cognitive impairment or dementia or for preventing recurrence of depression.. clinicaltrials.gov Identifier: NCT00177671.

Topics: Activities of Daily Living; Aged; Aged, 80 and over; Aging; Antidepressive Agents; Cholinesterase Inhibitors; Cognition; Depressive Disorder, Major; Donepezil; Double-Blind Method; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Indans; Male; Nootropic Agents; Piperidines; Secondary Prevention; Treatment Outcome

Clinical study results for neurokinin (NK) receptor antagonists in the treatment of depression have been mixed, with Phase III studies failing to fulfill the early promise demonstrated in Phase II studies. Casopitant, a selective NK1 antagonist that achieves nearly complete receptor occupancy was studied in 2 randomized, placebo-controlled, double-blind, Phase II trials in depressed outpatients to test the hypothesis that nearly complete NK1 receptor occupancy is required to achieve antidepressant efficacy. Study 092 used an interactive voice response system to recruit depressed patients with baseline Hamilton Depression (17-item, HAMD17) total scores higher than 24 who were randomized to fixed-dose casopitant 30 mg/d, 80 mg/d, or placebo for 8 weeks (n = 356). Study 096 required Carroll Depression Scale-Revised self-assessment scores of higher than 24 for randomization to casopitant 120 mg/d, paroxetine 30 mg/d (both reached via forced titration), or placebo for 8 weeks (n = 362). In study 092, casopitant 80 mg but not 30 mg achieved statistically significant improvement versus placebo on the primary outcome measure, week 8 last observation carried forward change from baseline HAMD17 (difference = -2.7; 95% confidence interval, -5.1 to -0.4, P = 0.023). In study 096, neither casopitant nor paroxetine achieved statistical separation from placebo at end point on HAMD17 (casopitant difference = -1.7; 95% CI, -3.8 to 0.4, P = 0.282). Casopitant and paroxetine were generally well tolerated in most patients. These studies suggest that NK1 antagonists that have nearly complete receptor occupancy may be effective in the treatment of depression.

Topics: Adult; Antidepressive Agents, Second-Generation; Depressive Disorder, Major; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Middle Aged; Neurokinin-1 Receptor Antagonists; Paroxetine; Piperazines; Piperidines; Psychiatric Status Rating Scales; Treatment Outcome

This randomized, placebo-controlled, double-blind study was the first to evaluate the antidepressant efficacy, safety, and tolerability of an NR2B subunit-selective N-methyl-D-aspartate receptor antagonist, CP-101,606. Subjects had major depression, according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria and a history of treatment refractoriness to least 1 adequate trial of a selective serotonin reuptake inhibitor. The study had 2 treatment periods. In period 1, subjects first received a 6-week open-label trial of paroxetine and a single-blind, intravenous placebo infusion. Period 1 nonresponders (n = 30) then received a randomized double-blind single infusion of CP-101,606 or placebo plus continued treatment with paroxetine for up to an additional 4 weeks (period 2). Depression severity was assessed using the Montgomery-Asberg Depression Rating Scale and 17-item Hamilton Depression Rating Scale. On the prespecified main outcome measure (change from baseline in the Montgomery-Asberg Depression Rating Scale total score at day 5 of period 2), CP-101,606 produced a greater decrease than did placebo (mean difference, 8.6; 80% confidence interval, -12.3 to -4.5) (P < 0.10). Hamilton Depression Rating Scale response rate was 60% for CP-101,606 versus 20% for placebo. Seventy-eight percent of CP-101,606-treated responders maintained response status for at least 1 week after the infusion. CP-101,606 was safe, generally well tolerated, and capable of producing an antidepressant response without also producing a dissociative reaction. Antagonism of the NR2B subtype of the N-methyl-D-aspartate receptor may be a fruitful target for the development of a new antidepressant with more robust effects and a faster onset compared with those currently available and capable of working when existing antidepressants do not.

Topics: Adult; Antidepressive Agents; Depressive Disorder, Major; Double-Blind Method; Drug Resistance; Excitatory Amino Acid Antagonists; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Paroxetine; Piperidines; Psychiatric Status Rating Scales; Receptors, N-Methyl-D-Aspartate; Research Design; Selective Serotonin Reuptake Inhibitors; Severity of Illness Index; Time Factors; Treatment Failure; Young Adult

We designed this prospective, randomized, double-blinded, placebo-controlled, crossover study to evaluate the effect of different doses of remifentanil on the acute hemodynamic response and duration of seizure activity after a standardized electroconvulsive therapy (ECT) stimulus. Twenty consenting patients with major depressive disorders receiving maintenance ECT participated in this study. Eighty ECT treatments were evaluated. All patients were premedicated with glycopyrrolate 0.2 mg IV, unconsciousness was induced with methohexital 1 mg/kg IV, and muscle paralysis was produced with succinylcholine 1.2 mg/kg IV. Subsequently, patients received 1 of 3 different doses of remifentanil 25, 50, and 100 microg or saline (control) in a random sequence immediately after methohexital at 4 consecutive ECT treatments. Labetalol, in 5-mg IV boluses, was used as a rescue antihypertensive medication. A fixed suprathreshold electrical stimulus was administered to elicit a seizure, and the times from the stimulus to the cessation of the motor and electroencephalographic (EEG) seizure activity were noted. Pre- and post-ECT blood pressure values were significantly decreased in the 100- microg remifentanil group compared with the control group. The durations of motor (38 +/- 9 s to 43 +/- 15 s) and EEG (55 +/- 29 s to 60 +/- 21 s) seizure activity were not significantly different among the four groups. Similarly, recovery times to eye opening, obeying commands, and discharge from the recovery room did not differ among the four study groups. The requirement for labetalol after ECT was nonsignificantly decreased in the remifentanil groups. In conclusion, remifentanil 100 microg IV attenuated the acute hemodynamic response to ECT. Furthermore, remifentanil had no adverse effect on the duration of ECT-induced seizure activity. Finally, adjunctive use of remifentanil did not prolong recovery times or increase post-ECT side effects.. Remifentanil (100 microg IV) attenuated the acute hemodynamic response after electroconvulsive therapy (ECT) without adversely affecting the length of the ECT-induced seizure activity or prolonging recovery times.

Topics: Adult; Aged; Aged, 80 and over; Anesthesia; Anesthesia, Intravenous; Anesthetics, Intravenous; Depressive Disorder, Major; Dose-Response Relationship, Drug; Double-Blind Method; Electroconvulsive Therapy; Electroencephalography; Female; Hemodynamics; Humans; Male; Middle Aged; Piperidines; Prospective Studies; Psychiatric Status Rating Scales; Remifentanil

Topics: Adult; Aged; Clinical Trials as Topic; Depressive Disorder, Major; Female; Humans; Long-Term Care; Male; Middle Aged; Obsessive-Compulsive Disorder; Penfluridol; Piperidines; Schizophrenia

Topics: Adolescent; Adult; Antidepressive Agents; Butyrophenones; Clinical Trials as Topic; Depressive Disorder, Major; Female; Fluorine; Humans; Light; Male; Middle Aged; Myoclonus; Perphenazine; Piperidines; Placebos; Reflex; Schizophrenia; Trifluperidol

In the 10-week, phase 2 CLARITY study of patients with major depressive disorder, adjunctive therapy to antidepressants with pimavanserin 34 mg once daily statistically significantly improved the Hamilton Depression Rating Scale (HAMD-17) total score (primary endpoint) and Sheehan Disability Scale (SDS) score (secondary endpoint) versus placebo. This analysis characterized the exposure-response (E-R) relationships of pimavanserin in this CLARITY patient population. Exposure measures were estimated for each patient based on population-pharmacokinetic empirical Bayesian estimates. E-R models were developed to describe exposure-efficacy (HAMD-17, SDS, and Clinical Global Impression-Improvement [CGI-I] scale) and exposure-safety relationships (Karolinska Sleepiness Scale [KSS], Massachusetts General Hospital Sexual Functioning Inventory [MGH-SFI], and adverse events [AEs] of headache, sedation, and somnolence) relationships. For the primary efficacy endpoint (HAMD-17 scores), a sigmoid maximum-effect model described the time course of response, and a linear function of pimavanserin exposure was statistically significant. HAMD-17 scores decreased steadily over time following placebo and pimavanserin treatment; separation from placebo increased as peak pimavanserin plasma concentration (C

Topics: Antidepressive Agents; Bayes Theorem; Depressive Disorder, Major; Humans; Piperidines

Previous studies have demonstrated a close association between an altered immune system and major depressive disorders, and inhibition of neuroinflammation may represent an alternative mechanism to treat depression. Recently, the anti-inflammatory activity of ibrutinib has been reported. However, the effect of ibrutinib on neuroinflammation-induced depression and its underlying mechanism has not been comprehensively studied. Therefore, we aimed to elucidate the potential anti-depressive role and mechanism of ibrutinib against neuroinflammation-induced depression and synaptic defects. Our results showed that ibrutinib treatment significantly reduced lipopolysaccharide (LPS)-induced depressive-like behaviors and neuroinflammation via inhibiting NF-kB activation, decreasing proinflammatory cytokine levels, and normalizing redox signaling and its downstream components, including Nrf2, HO-1, and SOD2, as well as glial cell activation markers, such as Iba-1 and GFAP. Further, ibrutinib treatment inhibited LPS-activated inflammasome activation by targeting NLRP3/P38/Caspase-1 signaling. Interestingly, LPS reduced the number of dendritic spines and expression of BDNF, and synaptic-related markers, including PSD95, snap25, and synaptophysin, were improved by ibrutinib treatment in the hippocampal area of the mouse brain. In conclusion, our findings suggest that ibrutinib can alleviate neuroinflammation and synaptic defects, suggesting it has antidepressant potential against LPS-induced neuroinflammation and depression.

Topics: Adenine; Animals; Depression; Depressive Disorder, Major; Inflammasomes; Lipopolysaccharides; Mice; Piperidines

Stress contributes to major depressive disorder (MDD) and chronic pain, which affect a significant portion of the global population, but researchers have not clearly determined how these conditions are initiated or amplified by stress. The chronic social defeat stress (CSDS) model is a mouse model of psychosocial stress that exhibits depressive-like behavior and chronic pain. We hypothesized that metabotropic glutamate receptor 5 (mGluR5) expressed in the nucleus accumbens (NAc) normalizes the depressive-like behaviors and pain following CSDS. Here, we show that CSDS induced both pain and social avoidance and that the level of mGluR5 decreased in susceptible mice. Overexpression of mGluR5 in the NAc shell and core prevented the development of depressive-like behaviors and pain in susceptible mice, respectively. Conversely, depression-like behaviors and pain were exacerbated in mice with mGluR5 knockdown in the NAc shell and core, respectively, compared to control mice subjected to 3 days of social defeat stress. Furthermore, (RS)-2-chloro-5-hydroxyphenylglycine (CHPG), an mGluR5 agonist, reversed the reduction in the level of the endocannabinoid (eCB) 2-arachidonoylglycerol (2-AG) in the NAc of susceptible mice, an effect that was blocked by 3-((2-methyl-1, 3-thiazol-4-yl) ethynyl) pyridine hydrochloride (MTEP), an mGluR5 antagonist. In addition, the injection of CHPG into the NAc shell and core normalized depressive-like behaviors and pain, respectively, and these effects were inhibited by AM251, a cannabinoid type 1 receptor (CB1R) antagonist. Based on these results, mGluR5-mediated eCB production in the NAc relieves stress-induced depressive-like behaviors and pain.

Topics: Animals; Cannabinoid Receptor Antagonists; Chronic Disease; Depressive Disorder, Major; Endocannabinoids; Male; Mice; Mice, Inbred C57BL; Microinjections; Nucleus Accumbens; Pain; Piperidines; Pyrazoles; Pyridines; Receptor, Metabotropic Glutamate 5; Signal Transduction; Social Defeat; Stress, Psychological; Thiazoles

Sexual dysfunction is common among patients with major depressive disorder (MDD). In the CLARITY study, the safety and efficacy of adjunctive pimavanserin, an inverse agonist at 5-HT. Patients with a diagnosis of MDD in a depressive episode, inadequate response to ongoing antidepressant therapy, and a Montgomery-Åsberg Depression Rating Scale total score >20 were randomized to pimavanserin 34 mg/day or placebo added to ongoing treatment with an immediate revision of all selective serotonin or serotonin-norepinephrine for 5 weeks (Stage 1), and nonresponders (<50% improvement from baseline in Hamilton Depression Rating Scale [HAMD-17]) were re-randomized for an additional 5 week (Stage 2). Effects of pimavanserin on the Massachusetts General Hospital Sexual Functioning Index (MGH-SFI) and HAMD-17 Item 14 (sexual interest) were examined.. Among 203 patients (51 on pimavanserin; 152 on placebo), pimavanserin demonstrated significant improvement from baseline to Week 5 on the MGH-SFI (least square [LS]mean difference -0.634, 95% confidence interval [CI] [-0.964, -0.304]; p = .0002; effect size [ES], Cohen's d: .614). Across Stages 1 and 2, the weighted LSmean difference was -0.468 (95% CI [-0.720, -0.216]; p = .0003) for pimavanserin versus placebo. Mean changes from baseline to Week 5 for MGH-SFI Items 1, 2, 3, and 5 and HAMD Item 14 were significantly (p < .05) greater with pimavanserin versus placebo.. Adjunctive pimavanserin improved sexual function in patients with MDD. Adding pimavanserin to ongoing treatment for MDD may be especially useful for patients experiencing sexual dysfunction.

Topics: Adult; Antidepressive Agents; Antipsychotic Agents; Depressive Disorder, Major; Double-Blind Method; Female; Humans; Longitudinal Studies; Male; Middle Aged; Norepinephrine; Piperidines; Selective Serotonin Reuptake Inhibitors; Serotonin; Sexual Dysfunction, Physiological; Treatment Outcome; Urea

Clinical and preclinical studies indicate that zinc (Zn) is an essential factor in the development and treatment of major depressive disorder (MDD). Conventional monoamine-based antidepressants mobilize zinc in the blood and brain of depressed patients as well as rodents. N-methyl-D-aspartate acid receptor (NMDAR) antagonists exhibit antidepressant-like activity. However, not much is known about the antidepressant efficacy of NMDAR antagonists in zinc-deficient (ZnD) animals. We evaluated the antidepressant-like activity of two NMDAR antagonists (ketamine; global NMDAR antagonist and Ro 25-6981 (Ro); selective antagonist of the GluN2B NMDAR subunit) in ZnD rats using the forced swim test (FST) and sucrose intake test (SIT). A single dose of either Ro 25-6981 or ketamine normalized depressive-like behaviors in ZnD rats; however, Ro was effective in both tests, while ketamine was only effective in the FST. Additionally, we investigated the mechanism of antidepressant action of Ro at the molecular (analysis of protein expression by Western blotting) and anatomical (density of dendritic spines by Golgi Cox-staining) levels. ZnD rats exhibited decreased phosphorylation of the p70S6K protein, and enhanced density of dendritic spines in the prefrontal cortex (PFC) compared to control rats. The antidepressant-like activity of Ro was associated with the increased phosphorylation of p70S6K and ERK in the PFC. In summary, single doses of the NMDAR antagonists ketamine and Ro exhibited antidepressant-like activity in the ZnD animal model of depression. Animals were only deprived of Zn for 4 weeks and the biochemical effects of Zn deprivation and Ro were investigated in the PFC and hippocampus. The shorter duration of dietary Zn restriction may be a limitation of the study. However, future studies with longer durations of dietary Zn restriction, as well as the investigation of multiple brain structures, are encouraged as a supplement to this study.

Topics: Analgesics; Animals; Behavior, Animal; Brain-Derived Neurotrophic Factor; Depressive Disorder, Major; Diet; Disease Models, Animal; Ketamine; Male; Phenols; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Zinc

Neurotransmitter substance P (SP) and its preferred neurokinin-1 receptor (NK1R) have been implicated in the treatment of affective and addiction disorders. Despite promising preclinical data on antidepressant action, the clinical trials of NK1R antagonists in major depression have been disappointing. There are no direct in vivo imaging studies on NK1R characteristics in patients with a major depressive disorder (MDD).. In this cross-sectional case-control study, we recruited nine never-medicated patients with moderate to severe MDD and nine matched healthy controls. NK1R availability (NK1R binding potential, BP. NK1R-BP. Small sample size. Low variability in the clinical HAM-D subscale ratings may affect the observed correlations.. Our preliminary results do not support a different baseline expression of NK1Rs in a representative sample of never-medicated patients with MDD during a current moderate/severe depressive episode. The modulatory effect of NK1Rs on affective symptoms is in line with early positive results on antidepressant action of NK1 antagonists. However, the effect is likely to be too weak for treatment of MDD with NK1R antagonists alone in clinical practice.

Topics: Adult; Antidepressive Agents; Anxiety; Brain Chemistry; Case-Control Studies; Cross-Sectional Studies; Depressive Disorder, Major; Female; Humans; Male; Middle Aged; Neurokinin-1 Receptor Antagonists; Neuronal Tract-Tracers; Pilot Projects; Piperidines; Positron-Emission Tomography; Receptors, Neurokinin-1; Tetrazoles

Alcohol use disorder (AUD) and major depressive disorder (MDD) are prevalent, debilitating, and highly comorbid disorders. The molecular changes that underlie their comorbidity are beginning to emerge. For example, recent evidence showed that acute ethanol exposure produces rapid antidepressant-like biochemical and behavioral responses. Both ethanol and fast-acting antidepressants block N-methyl-D-aspartate receptor (NMDAR) activity, leading to synaptic changes and long-lasting antidepressant-like behavioral effects. We used RNA sequencing to analyze changes in the synaptic transcriptome after acute treatment with ethanol or the NMDAR antagonist, Ro 25-6981. Ethanol and Ro 25-6981 induced differential, independent changes in gene expression. In contrast with gene-level expression, ethanol and Ro 25-6981 produced overlapping changes in exons, as measured by analysis of differentially expressed exons (DEEs). A prominent overlap in genes with DEEs indicated that changes in exon usage were important for both ethanol and Ro 25-6981 action. Structural modeling provided evidence that ethanol-induced exon expression in the NMDAR1 amino-terminal domain could induce conformational changes and thus alter NMDAR function. These findings suggest that the rapid antidepressant effects of ethanol and NMDAR antagonists reported previously may depend on synaptic exon usage rather than gene expression.

Topics: Alcoholism; Alternative Splicing; Animals; Antidepressive Agents; Comorbidity; Depressive Disorder, Major; Ethanol; Exons; Gene Expression; Hippocampus; Male; Mice, Inbred C57BL; Models, Animal; Phenols; Piperidines; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Transcriptome

Topics: Animals; Antidepressive Agents; Brain; Brain Mapping; Depressive Disorder, Major; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Ketamine; Magnetic Resonance Imaging; Male; Nonlinear Dynamics; Phenols; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Wakefulness

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Topics: Administration, Intravenous; Allosteric Regulation; Animals; Antidepressive Agents; Brain; Brain Waves; Depressive Disorder, Major; Dissociative Disorders; Macaca fascicularis; Male; Memory, Short-Term; Mice; Motor Activity; Organophosphates; Piperidines; Prodrugs; Pyrrolidinones; Radioligand Assay; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Xenopus

Topics: Antidepressive Agents; Depressive Disorder, Major; Female; Humans; Hyponatremia; Middle Aged; Piperazines; Piperidines; Psychotic Disorders

The 5-HT4 receptor provides a novel potential target for antidepressant treatment. No studies exist to elucidate the 5-HT4 receptor's in vivo distribution in the depressed state or in populations that may display trait markers for major depression disorder (MDD). The aim of this study was to determine whether familial risk for MDD is associated with cerebral 5-HT4 receptor binding as measured with [(11)C]SB207145 brain PET imaging. Familial risk is the most potent risk factor of MDD.. We studied 57 healthy individuals (mean age 36 yrs, range 20-86; 21 women), 26 of which had first-degree relatives treated for MDD.. We found that having a family history of MDD was associated with lower striatal 5-HT4 receptor binding (p = 0.038; in individuals below 40 years, p = 0.013). Further, we found evidence for a "risk-dose effect" on 5-HT4 receptor binding, since the number of first-degree relatives with a history of MDD binding correlated negatively with 5-HT4 receptor binding in both the striatum (p = 0.001) and limbic regions (p = 0.012).. Our data suggest that the 5-HT4 receptor is involved in the neurobiological mechanism underlying familial risk for depression, and that lower striatal 5-HT4 receptor binding is associated with increased risk for developing MDD. The finding is intriguing considering that the 5-HT4 receptor has been suggested to be an effective target for antidepressant treatment.

Topics: Adult; Aged; Aged, 80 and over; Brain; Carbon Radioisotopes; Depressive Disorder, Major; Family; Female; Genetic Predisposition to Disease; Humans; Male; Middle Aged; Piperidines; Positron-Emission Tomography; Protein Binding; Radiopharmaceuticals; Receptors, Serotonin, 5-HT4; Serotonin Plasma Membrane Transport Proteins; Young Adult

Given increased knowledge from molecular biology and pharmacology, it is apparent that multiple factors can interact to produce clinically meaningful differences in a drug's effect in specific individuals (i.e., personalized medicine). This topic is discussed in this column using iloperidone as an example. The variables discussed include dose, dosing schedule, genes, drug-drug interactions, and other medical factors. How such variables can combine to alter a drug's effect is illustrated with a case example and the results of a thorough QTc study of iloperidone.

Topics: Affective Disorders, Psychotic; Aged; Antipsychotic Agents; Depressive Disorder, Major; Dizziness; Drug Interactions; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels; Humans; Isoxazoles; Male; Paroxetine; Pharmacogenetics; Piperidines; Precision Medicine

Although a reduced dose of propofol combined with remifentanil is often used in anesthesia for electroconvulsive therapy (ECT), there have been few studies in which the optimal technique for injection of remifentanil was examined in detail. The aim of this study was to evaluate the effects of single and divided injection of remifentanil combined with propofol on seizure duration and hemodynamic responses during ECT.. Twenty-six ASA I-II patients were enrolled in this study and received a total of 78 ECTs. Each patient received propofol 1.2 mg/kg (group P), remifentanil 1 μg/kg followed by propofol 0.5 mg/kg (group R1), and remifentanil 1 μg/kg followed by propofol 0.5 mg/kg and thereafter remifentanil 2 μg/kg (group R2). Succinylcholine 1 mg/kg was used for muscle paralysis after loss of consciousness.. Although mean motor seizure durations were significantly longer in groups R1 and R2 than in group P (P < 0.05), they were similar in groups R1 and R2. Although the percentage increases in mean arterial pressure after ECT were significantly smaller in groups P (P < 0.01) and R2 (P < 0.05) than in group R1, they did not significantly differ between groups P and R2.. Divided use of remifentanil at 1 and 2 μg/kg combined with propofol 0.5 mg/kg produces an acceptable outcome in both seizure duration and hemodynamic stability during ECT compared with the standard hypnotic doses of propofol alone or remifentanil 1 μg/kg followed by propofol 0.5 mg/kg.

Topics: Adult; Aged; Anesthesia, Intravenous; Anesthetics, Intravenous; Depressive Disorder, Major; Dose-Response Relationship, Drug; Electroencephalography; Electroshock; Female; Hemodynamics; Humans; Male; Middle Aged; Piperidines; Preanesthetic Medication; Propofol; Remifentanil; Schizophrenia; Seizures

Topics: Adult; Alzheimer Disease; Atrophy; Cholinesterase Inhibitors; Cognition Disorders; Depressive Disorder, Major; Diagnosis, Differential; Donepezil; Drug Therapy, Combination; Female; Follow-Up Studies; Functional Laterality; Hippocampus; Humans; Indans; Magnetic Resonance Imaging; Piperidines; Selective Serotonin Reuptake Inhibitors; Sertraline; Treatment Outcome

Topics: Antidepressive Agents; Depressive Disorder, Major; Double-Blind Method; Drug Resistance; Excitatory Amino Acid Antagonists; Humans; Infusions, Intravenous; Paroxetine; Piperidines; Psychiatric Status Rating Scales; Randomized Controlled Trials as Topic; Receptors, N-Methyl-D-Aspartate; Receptors, sigma; Research Design; Sigma-1 Receptor; Treatment Outcome

Topics: Adult; Antidepressive Agents; Antipsychotic Agents; Depressive Disorder, Major; Drug Resistance; Drug Therapy, Combination; Female; Humans; Piperazines; Piperidines; Treatment Outcome

Topics: Anti-Obesity Agents; Depression; Depressive Disorder, Major; Humans; Obesity; Patient Selection; Piperidines; Pyrazoles; Rimonabant; Suicide

Topics: Anti-Obesity Agents; Depression; Depressive Disorder, Major; Humans; Obesity; Piperidines; Pyrazoles; Rimonabant

Delirium and agitation are commonly encountered after administration of electroconvulsive therapy (ECT). Management is generally fairly straightforward, although some patients may have a severe, prolonged, or refractory course. We recently cared for a 65-year-old man who consistently developed severe and very prolonged post-ECT delirium that did not respond to typical pharmacological agents; the duration of delirium was dramatically shortened by the addition of donepezil. Cholinesterase inhibitors may have a place in mitigating severe and prolonged post-ECT delirium.

Topics: Aged; Cholinesterase Inhibitors; Delirium; Depressive Disorder, Major; Donepezil; Electroconvulsive Therapy; Humans; Indans; Male; Piperidines; Psychomotor Agitation

The efficacy of antidepressants has been linked in part to their ability to reduce activity of the hypothalamic-pituitary-adrenal (HPA) axis; however, the mechanism by which antidepressants regulate the HPA axis is largely unknown. Given that recent research has demonstrated that endocannabinoids can regulate the HPA axis and exhibit antidepressant potential, we examined the hypothesis that the endocannabinoid system is regulated by long-term antidepressant treatment. Three-week administration of the tricyclic antidepressant desipramine (10 mg/kg/day) resulted in a significant increase in the density of the cannabinoid CB(1) receptor in the hippocampus and hypothalamus, without significantly altering endocannabinoid content in any brain structure examined. Furthermore, chronic desipramine treatment resulted in a reduction in both secretion of corticosterone and the induction of the immediate early gene c-fos in the medial dorsal parvocellular region of the paraventricular nucleus of the hypothalamus (PVN) following a 5 min exposure to swim stress. Acute treatment with the CB(1) receptor antagonist, AM251 (1 mg/kg), before exposure to swim stress, completely occluded the ability of desipramine to reduce both corticosterone secretion and induction of c-fos expression in the PVN. Collectively, these data demonstrate that CB(1) receptor density in the hippocampus and hypothalamus is increased by chronic tricyclic antidepressant treatment, and suggest that this upregulation could contribute to the ability of tricyclic antidepressants to suppress stress-induced activation of the HPA axis.

Topics: Animals; Antidepressive Agents, Tricyclic; Cannabinoid Receptor Modulators; Cortisone; Depressive Disorder, Major; Desipramine; Disease Models, Animal; Drug Administration Schedule; Endocannabinoids; Gene Expression Regulation; Hippocampus; Hypothalamo-Hypophyseal System; Male; Norepinephrine; Paraventricular Hypothalamic Nucleus; Piperidines; Proto-Oncogene Proteins c-fos; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Stress, Psychological; Up-Regulation

Electroconvulsive therapy (ECT) is standard treatment of severe depression. The induction of a seizure is a core event in successful ECT. Although propofol is a frequently used anesthetic agent, one of its limitations is a reduction of seizure duration. No such effects have been reported regarding remifentanil, an ultrarapid-acting opioid that is used to induce and maintain anesthesia. The simultaneous administration of propofol and remifentanil may have similar safety and efficacy in terms of induction of anesthesia during ECT as propofol alone and significantly increase seizure duration.. Twenty-one ECT patients (10 men, 11 women, aged 24 to 81 years) were recruited. Muscle paralysis was achieved with succinylcholine (0.5-0.75 mg/kg intravenously [IV]). Unconsciousness was induced by either propofol (1 mg/kg IV) or propofol (0.5 mg/kg IV) + remifentanil (1 microg/kg) in a crossover format. ECT was administered according to established clinical protocols at the Sheba Medical Center, Israel. No changes in ECT current were permitted in the 2 protocols of each patient. Statistical analysis was based on paired t tests.. In all but 2 cases, seizure duration was significantly longer in the remifentanil group than in the control group (motor seizure 53.7 +/- 28.3 seconds vs. 29.5 +/- 10.9 seconds, t = 4.017, P = 0.0007; Electroencephalographic (EEG) seizures 60.8 +/- 25.1 seconds vs. 40.1 +/- 17.0 seconds, t = 3.971, P = 0.001). No significant differences were found in mean recovery time, post-treatment elevation in blood pressure, heart-beat, or oxygen saturation.. During anesthesia, the addition of remifentanil to propofol appears to be as effective as propofol alone with regard to anesthesia efficacy and cardiovascular function while significantly increasing seizure duration. Whether this discovery is of relevance to the clinical efficacy of ECT remains to be tested.

Topics: Adult; Aged; Aged, 80 and over; Anesthetics, Intravenous; Depressive Disorder, Major; Electroconvulsive Therapy; Female; Hemodynamics; Humans; Male; Middle Aged; Piperidines; Propofol; Remifentanil; Schizophrenia; Seizures; Time Factors

Centrally active cholinergic agents such as arecoline and physostigmine shorten rapid eye movement (REM) latency, reduce REM interval times, or both and do so preferentially in patients with depression. We tested an orally administered cholinergic agonist (donepezil HCL 10 mg [Aricept]) to determine whether this agent also alters REM timing in depressed patients (n = 8) compared with age- and gender-matched control subjects (n = 8).. All subjects were studied for 3 consecutive nights in the sleep laboratory. The design was a fixed-order placebo-donepezil protocol to accommodate the long half-life of donepezil. Night 1 served as an adaptation night. On night 2, placebo was administered at 8:00 PM. On night 3, donepezil was administered at 8:00 PM.. The cholinergic challenge distinguished the groups. In depressed patients REM latency was reduced compared with baseline (47.6 vs. 64.4, p =.04) following administration of donepezil. Control subjects showed no response: REM latency after donepezil was virtually identical to baseline REM latency (71.7 vs. 69.3).. These data indicate that donepezil is likely to be useful in testing hypotheses related to cholinergic function in mood disorders.

Topics: Administration, Oral; Adult; Cholinergic Agents; Cholinesterase Inhibitors; Depressive Disorder, Major; Donepezil; Female; Humans; Indans; Male; Middle Aged; Piperidines; Polysomnography; Reaction Time; Single-Blind Method; Sleep, REM

Topics: Aged; Bipolar Disorder; Cholinesterase Inhibitors; Depressive Disorder, Major; Donepezil; Female; Humans; Indans; Male; Piperidines

Topics: Adult; Aged; Antidepressive Agents; Antidepressive Agents, Tricyclic; Depressive Disorder; Depressive Disorder, Major; Dibenzocycloheptenes; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Piperidines

Topics: Analgesics; Depressive Disorder, Major; Female; Hallucinations; Humans; Methadone; Middle Aged; Piperidines

Topics: Adult; Aged; Autistic Disorder; Delusions; Depressive Disorder, Major; Female; Humans; Male; Mental Disorders; Paranoid Disorders; Piperidines; Schizophrenia; Spiro Compounds; Time Factors; Tranquilizing Agents

Topics: 1-Propanol; Adjustment Disorders; Adult; Aged; Antidepressive Agents; Antiparkinson Agents; Anxiety Disorders; Basal Ganglia Diseases; Biperiden; Bipolar Disorder; Delayed-Action Preparations; Depression; Depressive Disorder, Major; Female; Humans; Mental Disorders; Middle Aged; Paranoid Disorders; Piperidines; Schizophrenia, Disorganized; Tranquilizing Agents; Tremor

Topics: Bipolar Disorder; Chlorpromazine; Depression; Depressive Disorder, Major; Methylphenidate; Piperidines; Psychotic Disorders