Assessment of Objective and Subjective Cognitive Function in Patients With Treatment-Resistant Depression Undergoing Repeated Ketamine Infusions

BackgroundSubanesthetic ketamine infusions can elicit rapid and sustained antidepressant effects, yet the potential cognitive impact of ketamine has not been thoroughly examined. This study measured changes in objective and subjective cognitive function following repeated ketamine treatment.MethodsThirty-eight patients with treatment-resistant depression were administered cognitive assessments before and after undergoing 7 i.v. ketamine infusions (0.5 mg/kg over 40 minutes) within a clinical trial examining the efficacy of single and repeated administrations. Depression severity and perceived concentration were evaluated with the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Quick Inventory of Depressive Symptoms Self-Report.ResultsTwenty-three participants (60.5%) responded after repeated infusions (≥50% decrease in MADRS total scores). We measured significant improvements in several cognitive domains, including attention, working memory, verbal, and visuospatial memory (effect sizes ranging from Cohen d = 0.37–0.79). Cognitive changes were attributed to reduction in depressive symptoms except for improvement in verbal memory, which remained significant after adjustment for change in MADRS total score (P = .029, η _p²=0.13). Only responders reported improvement in subjective cognitive function with repeated ketamine administration (MADRS item 6, P < .001, d = 2.00; Quick Inventory of Depressive Symptoms Self-Report item 10, P < .001, d = 1.36).ConclusionA short course of repeated ketamine infusions did not impair neurocognitive function in patients with treatment-resistant depression. Further research is required to understand the potential mediating role of response and remission on improved cognitive function accompanying ketamine treatment as well as to examine longer-term safety outcomes. ClinicalTrials.gov identifier {"type":"clinical-trial","attrs":{"text":"NCT01945047","term_id":"NCT01945047"}}NCT01945047     

Racemic Ketamine as an Alternative to Electroconvulsive Therapy for Unipolar Depression: A Randomized,Open-Label,Non-Inferiority Trial (KetECT)

BackgroundKetamine has emerged as a fast-acting and powerful antidepressant, but no head to head trial has been performed, Here, ketamine is compared with electroconvulsive therapy (ECT), the most effective therapy for depression.MethodsHospitalized patients with unipolar depression were randomized (1:1) to thrice-weekly racemic ketamine (0.5 mg/kg) infusions or ECT in a parallel, open-label, non-inferiority study. The primary outcome was remission (Montgomery Åsberg Depression Rating Scale score ≤10). Secondary outcomes included adverse events (AEs), time to remission, and relapse. Treatment sessions (maximum of 12) were administered until remission or maximal effect was achieved. Remitters were followed for 12 months after the final treatment session.ResultsIn total 186 inpatients were included and received treatment. Among patients receiving ECT, 63% remitted compared with 46% receiving ketamine infusions (P = .026; difference 95% CI 2%, 30%). Both ketamine and ECT required a median of 6 treatment sessions to induce remission. Distinct AEs were associated with each treatment. Serious and long-lasting AEs, including cases of persisting amnesia, were more common with ECT, while treatment-emergent AEs led to more dropouts in the ketamine group. Among remitters, 70% and 63%, with 57 and 61 median days in remission, relapsed within 12 months in the ketamine and ECT groups, respectively (P = .52).ConclusionRemission and cumulative symptom reduction following multiple racemic ketamine infusions in severely ill patients (age 18–85 years) in an authentic clinical setting suggest that ketamine, despite being inferior to ECT, can be a safe and valuable tool in treating unipolar depression.     

Ketamine for Bipolar Depression: A Systematic Review

BackgroundKetamine appears to have a therapeutic role in certain mental disorders, most notably unipolar major depressive disorder. However, its efficacy in bipolar depression is less clear. This study aimed to assess the efficacy and tolerability of ketamine for bipolar depression.MethodsWe conducted a systematic review of experimental studies using ketamine for the treatment of bipolar depression. We searched PubMed, MEDLINE, Embase, PsycINFO, and the Cochrane Central Register for relevant studies published since each database’s inception. We synthesized evidence regarding efficacy (improvement in depression rating scores) and tolerability (adverse events, dissociation, dropouts) across studies.ResultsWe identified 6 studies, with 135 participants (53% female; 44.7 years; standard deviation, 11.7 years). All studies used 0.5 mg/kg of add-on intravenous racemic ketamine, with the number of doses ranging from 1 to 6; all participants continued a mood-stabilizing agent. The overall proportion achieving a response (defined as those having a reduction in their baseline depression severity of at least 50%) was 61% for those receiving ketamine and 5% for those receiving a placebo. The overall response rates varied from 52% to 80% across studies. Ketamine was reasonably well tolerated; however, 2 participants (1 receiving ketamine and 1 receiving placebo) developed manic symptoms. Some participants developed significant dissociative symptoms at the 40-minute mark following ketamine infusion in 2 trials.ConclusionsThere is some preliminary evidence supporting use of intravenous racemic ketamine to treat adults with bipolar depression. There is a need for additional studies exploring longer-term outcomes and alterative formulations of ketamine.     

Course of Improvement in Depressive Symptoms to a Single Intravenous Infusion of Ketamine vs Add-on Riluzole: Results from a 4-Week,Double-Blind,Placebo-Controlled Study

The N-methyl--aspartate antagonist ketamine has rapid antidepressant effects in patients with treatment-resistant major depression (TRD); these effects have been reported to last for 1 week in some patients. However, the extent and duration of this antidepressant effect over longer periods has not been well characterized under controlled conditions. Riluzole, a glutamatergic modulator with antidepressant and synaptic plasticity-enhancing effects, could conceivably be used to promote the antidepressant effects of ketamine. This study sought to determine the extent and time course of antidepressant improvement to a single-ketamine infusion over 4 weeks, comparing the addition of riluzole vs placebo after the infusion. Forty-two subjects (18–65) with TRD and a Montgomery–Asberg Depression Rating Scale (MADRS) score of ⩾22 received a single intravenous infusion of ketamine (0.5 mg/kg). Four to six hours post-infusion, subjects were randomized to double-blind treatment with either riluzole (100–200 mg/day; n=21) or placebo (n=21) for 4 weeks. Depressive symptoms were rated daily. A significant improvement (P<0.001) in MADRS scores from baseline was found. The effect size of improvement with ketamine was initially large and remained moderate throughout the 28-day trial. Overall, 27% of ketamine responders had not relapsed by 4 weeks following a single ketamine infusion. The average time to relapse was 13.2 days (SE=2.2). However, the difference between the riluzole and placebo treatment groups was not significant, suggesting that the combination of riluzole with ketamine treatment did not significantly alter the course of antidepressant response to ketamine alone.     

Vortioxetine: a review of efficacy,safety and tolerability with a focus on cognitive symptoms in major depressive disorder

Introduction: Vortioxetine is a pharmacodynamically novel antidepressant that exerts effects on various neurotransmitters including serotonin, noradrenaline, dopamine, glutamate, histamine and acetylcholine. Its efficacy in the symptomatic management of major depressive disorder (MDD) has been established in several short- and long-term trials. Vortioxetine has also demonstrated independent pro-cognitive effects in adults with MDD.

Areas covered: This report provides a concise review of the pharmacology, efficacy and safety of vortioxetine as they pertain to cognition.

Expert opinion: The significant impact of cognitive dysfunction in MDD has achieved increased consideration among researchers over the past decade. Vortioxetine is the first antidepressant agent to demonstrate meaningful clinical efficacy in the improvement of cognition in adults with MDD, independent of improvement in affective symptomatology. These results provide the impetus for further study into the potential pro-cognitive effects of vortioxetine in other conditions wherein cognitive dysfunction is prominent.     

Predicting Antidepressant Effects of Ketamine: the Role of the Pregenual Anterior Cingulate Cortex as a Multimodal Neuroimaging Biomarker

BackgroundGrowing evidence underscores the utility of ketamine as an effective and rapid-acting treatment option for major depressive disorder (MDD). However, clinical outcomes vary between patients. Predicting successful response may enable personalized treatment decisions and increase clinical efficacy.MethodsWe here explored the potential of pregenual anterior cingulate cortex (pgACC) activity to predict antidepressant effects of ketamine in relation to ketamine-induced changes in glutamatergic metabolism. Prior to a single i.v. infusion of ketamine, 24 patients with MDD underwent functional magnetic resonance imaging during an emotional picture-viewing task and magnetic resonance spectroscopy. Changes in depressive symptoms were evaluated using the Beck Depression Inventory measured 24 hours pre- and post-intervention. A subsample of 17 patients underwent a follow-up magnetic resonance spectroscopy scan.ResultsAntidepressant efficacy of ketamine was predicted by pgACC activity during emotional stimulation. In addition, pgACC activity was associated with glutamate increase 24 hours after the ketamine infusion, which was in turn related to better clinical outcome.ConclusionsOur results add to the growing literature implicating a key role of the pgACC in mediating antidepressant effects and highlighting its potential as a multimodal neuroimaging biomarker of early treatment response to ketamine.     

Resting Glutamate Levels and Rapid Glutamate Transients in the Prefrontal Cortex of the Flinders Sensitive Line Rat: A Genetic Rodent Model of Depression

Despite the numerous drugs targeting biogenic amines for major depressive disorder (depression), the search for novel therapeutics continues because of their poor response rates (∼30%) and slow onset of action (2–4 weeks). To better understand role of glutamate in depression, we used an enzyme-based microelectrode array (MEA) that was selective for glutamate measures with fast temporal (2 Hz) and high spatial (15 × 333 μm) resolution. These MEAs were chronically implanted into the prefrontal cortex of 3- to 6-month-old and 12- to 15-month-old Flinders Sensitive Line (FSL) and control Flinders Resistant Line (FRL) rats, a validated genetic rodent model of depression. Although no changes in glutamate dynamics were observed between 3 and 6 months FRL and FSL rats, a significant increase in resting glutamate levels was observed in the 12- to 15-month-old FSL rats compared with the 3- to 6-month-old FSL and age-matched FRL rats on days 3–5 post-implantation. Our MEA also recorded, for the first time, a unique phenomenon in all the four rat groups of fluctuations in resting glutamate, which we have termed glutamate transients. Although these events lasted only for seconds, they did occur throughout the testing paradigm. The average concentration of these glutamate-burst events was significantly increased in the 12- to 15-month-old FSL rats compared with 3- to 6-month-old FSL and age-matched FRL rats. These studies lay the foundation for future studies of both tonic and phasic glutamate signaling in rat models of depression to better understand the potential role of glutamate signaling in depression.     

Basimglurant for treatment of major depressive disorder: a novel negative allosteric modulator of metabotropic glutamate receptor 5

Introduction: Metabotropic glutamate receptor 5 (mGlu5) negative allosteric modulators (NAM) such as 2-Methyl-6-(phenylethynyl)pyridine (MPEP) and 3-((2-Methyl-1,3-thiazol-4-yl)ethynyl)pyridine (MTEP) can produce antidepressant-like effects; an example being the forced swim test in rodents. It is therefore of high interest that a new mGlu5 NAM called basimglurant (RO4917523, RG7090) was recently introduced for clinical development in depression.

Areas covered: The current article reports on the preclinical and clinical work with basimglurant which strongly supports its use for treatment of depression. The authors cover the pharmacodynamics, pharmacokinetics and safety and tolerability features of basimglurant together with its clinical efficacy in a clinical type II trial.

Expert opinion: The antidepressant activity of basimglurant may be related to a preferential reduction of mGlu5 receptor signaling in distinct populations of cortical limbic GABA interneurons causing disinhibition of discrete glutamate neuronal networks in brain circuits of mood and emotion. Basimglurant’s removal of mGlu5 receptor induced inhibition of D2 receptor signaling in A2A-D2-mGlu5 heteroreceptor complexes of ventral striato-pallidal GABA neurons mediating anti-reward may also play a role. Basimglurant is a highly promising antidepressant drug now in clinical development for depression. However, further clinical trials are highly warranted.     

Duloxetine versus escitalopram and placebo in the treatment of patients with major depressive disorder: onset of antidepressant action,a non-inferiority study*

ABSTRACT

Objective: The goal of a non-inferiority study is to test whether a new treatment has at least as much efficacy as an established treatment¹. The purpose of this non-inferiority study was to compare the speed of onset of antidepressant efficacy for duloxetine (a dual serotonin and norepinephrine reuptake inhibitor) and escitalopram (a selective serotonin reuptake inhibitor).

Research design and methods: This was a randomized, double-blind, placebo- and active comparator-controlled study, in which patients (≥ 18 years) meeting DSM?IV criteria for Major Depressive Disorder (MDD) received duloxetine 60?mg once daily (QD; N = 273), escitalopram 10?mg QD (N = 274), or placebo (N = 137) for 8 weeks. The primary objective was to compare the onset of antidepressant efficacy, by testing the hypothesis that the percentage of duloxetine-treated patients achieving onset criteria at Week 2 was not inferior to that in the escitalopram group.

Main outcome measures: Onset of efficacy was defined as a 20% decrease from baseline on the 17?item Hamilton Rating Scale for Depression (HAMD₁₇) Maier subscale that was maintained or exceeded at all subsequent visits.

Results: Probabilities of meeting onset criteria at Week 2 for duloxetine- and escitalopram-treated patients were 42.6% versus 35.2%, respectively (treatment difference = 7.4%; 95% confidence interval, –1.3% to 16.2%; p = 0.097). Both drugs showed significant improvement compared with placebo (?p ≤ 0.05) on the primary efficacy measure (Maier subscale) at Week 1 and endpoint (Week 8). No differences were found between duloxetine, escitalopram, and placebo rates of remission or response at 8 weeks. Adverse events that occurred significantly more frequently among duloxetine-treated patients when compared with those receiving escitalopram were nausea, dry mouth, vomiting, yawning, and irritability. The rate of discontinuation due to adverse events did not differ significantly between treatment groups.

Limitations: Given the difficulties in constructing appropriate dose comparisons, the results of this study should be interpreted specific to the doses tested and not extrapolated to the drug as a whole. This study employed a fixed-dose design; flexible-dose designs are more likely to find a difference between antidepressants and placebo.

Conclusion: In this study, both duloxetine and escitalopram showed significantly greater improvement on the primary efficacy measure than placebo over the 8?week acute treatment period, while no differences were observed between drugs or between drugs and placebo on response and remission rates at 8 weeks. Escitalopram at a starting dose of 10?mg QD was better tolerated than duloxetine at a starting dose of 60?mg QD. This study met its pre-defined primary objective of assessing if duloxetine was non-inferior to escitalopram in antidepressant onset efficacy, and the results show that duloxetine is at least as fast as (non-inferior to) escitalopram.

Trial registration: ClinicalTrials.gov identifier: NCT00073411.     

Vortioxetine: a novel antidepressant for the treatment of major depressive disorder

Introduction: Vortioxetine is a novel antidepressant drug approved for the treatment of major depressive disorder (MDD) in adults. It is formulated into tablets and has a dose range of 5–20 mg. The recommended starting dose is 10 mg administered orally once daily without the need for food.

Areas covered: This review focuses on the preclinical and clinical discovery of vortioxetine. It analyzes the pharmacological, neurochemical, and behavioral mechanisms of the medication and how these contribute to its potential therapeutic advantages as described in published preclinical and clinical studies and product labels.

Expert opinion: Vortioxetine displays high affinity for serotonin transporter (SERT), and serotonin 5-HT₃, 5HT_1A, 5HT₇ receptors. Functional studies show that vortioxetine acts as a SERT blocker, a 5-HT₃, 5-HT₇ receptor antagonist, and a 5-HT_1A receptor agonist. The drug is active in animal models predictive of antipsychotic and antidepressant activities and demonstrates procognitive effects in several animal models that assessed memory, cognition, and executive functions. Short- and long-term clinical trials demonstrated the clinical efficacy of vortioxetine in treating depressive symptoms and cognitive deficits in MDD patients. It also displays fairly benign safety and tolerability profiles. Vortioxetine’s unique psychopharmacological properties might contribute to an improved clinical outcome in MDD patient populations.     

Mood Therapeutics: Novel Pharmacological Approaches for Treating Depression

Introduction: Real-world effectiveness trials suggest that antidepressant efficacy is limited in many patients with mood disorders, underscoring the urgent need for novel therapeutics to treat these disorders.

Areas covered: Here, we review the clinical evidence supporting the use of novel modulators for the treatment of mood disorders, including specific glutamate modulators such as: 1) high-trapping glutamatergic modulators; 2) subunit (NR2B)-specific N-methyl-D-aspartate (NMDA) receptor antagonists; 3) NMDA receptor glycine-site partial agonists; and 4) metabotropic glutamate receptor (mGluR) modulators. We also discuss other promising, non-glutamatergic targets for potential rapid antidepressant effects in mood disorders, including the cholinergic system, the glucocorticoid system, and the inflammation pathway, as well as several additional targets of interest. Clinical evidence is emphasized, and non-pharmacological somatic treatments are not reviewed. In general, this paper only explores agents available in the United States.

Expert commentary: Of these novel targets, the most promising – and the ones for whom the most evidence exists – appear to be the ionotropic glutamate receptors. However, moving forward will require us to fully embrace the goal of personalized medicine and will require health professionals to pre-emptively identify potential responders.     

Neurofilament Light Chain Is a Novel Biomarker for Major Depression and Related Executive Dysfunction

BackgroundEvidence suggests that major depressive disorder is related to neuroaxonal injury and that neurofilament light chain (NfL) is a biomarker of neuroaxonal injury. In addition, proinflammatory cytokines have been reported to be associated with major depression and neuroaxonal injury.MethodsForty patients with major depression and 40 age- and sex-matched healthy control participants were enrolled for the measurement of NfL and proinflammatory cytokines and assessment of executive function. General linear models were used to examine the association between NfL levels, proinflammatory cytokine levels, and executive function.ResultsPatients with major depressive disorder exhibited significantly higher NfL levels (P = .007) than the control participants. NfL levels were positively related to log-transformed levels of tumor necrosis factor-α (P = .004). Higher levels of NfL (P = .002) and tumor necrosis factor-α (P = .013) were associated with greater deficits in executive function.DiscussionNfL was a novel biomarker for major depressive disorder and related executive dysfunction. Further studies are necessary to elucidate the role of NfL in the pathophysiology of major depression and related cognitive impairment.     

Pharmacotherapy and nutritional supplements for seasonal affective disorders: a systematic review

Introduction: A seasonal affective disorder (SAD) is a subtype of unipolar and bipolar major depressive disorders. It is characterized by its annual recurrence of depressive episodes at a particular season, mostly seen in winter and is responsible for 10–20% of the prevalence of major depressive disorders. Some pathophysiological hypotheses, such as the phase delay and the monoamine depletion hypotheses, have been postulated but the exact cause has not been fully unraveled yet. Studies on treatment for SAD in the last decade are lacking. To tackle this chronic disease, attention needs to be drawn to the gaps in this research field.

Areas covered: In this systematic review, the authors give a broad overview of the pharmacological therapy available for SAD. Also, nutritional substances fitting well with the postulated hypotheses are reviewed for the treatment and prevention of SAD. There is a specific focus on the quality of the currently performed studies.

Expert opinion: Light therapy and fluoxetine are the only proven and effective acute treatment options for SAD, while bupropion is the only registered drug for prevention of SAD. This area of research is in dire need of valid large-scale and sufficiently reproducible randomized control trials.     

Undertreatment of hypercholesterolaemia: a population-based study

AIMS: To assess the level of undertreatment of hypercholesterolaemia in the general population, taking intra-person variability in serum cholesterol concentrations into account, and to identify determinants of undertreatment of hypercholesterolaemia. METHODS: In this cross-sectional study, data from two population-based surveys on cardiovascular disease risk factors conducted between 1987 and 1997 in the Netherlands were used. For all 64 757 respondents aged 20-59 years, treatment eligibility for lipid-lowering drug use was established according to the Dutch Cholesterol Consensus. Multivariate logistic models were used to identify determinants of undertreatment. RESULTS: During the study period, 56.8% of the study population had undesirable cholesterol concentrations (serum total cholesterol> 5 mmol l(-1)) and 5.5% of those were eligible for pharmacological treatment based on their absolute risk of coronary heart disease. Of those eligible for pharmacological treatment, 16.3% were treated, and 19.6% of those treated had their serum total cholesterol concentration controlled. Only 3.2% of those eligible for pharmacological treatment were both treated and controlled. We identified several determinants for undertreatment, e.g. male gender and younger age for primary prevention and female gender and older age for secondary prevention. Treatment has improved slightly in more recent years. CONCLUSIONS: Over 95% of the population eligible for the pharmacological treatment of hypercholesterolaemia was either untreated or was uncontrolled. To decrease undertreatment, identification of high-risk patients should be increased. Those who are treated with lipid-lowering medication could further benefit from more aggressive treatment, especially with statins.     

Drugs to Be Used With a Filter for Preparation and/or Administration—2019

This chart is an update to the 2012 article published in Hospital Pharmacy on injectable drugs to be used with a filter. To update the chart, drugs approved from December 2011 to April 2019 were reviewed to determine if they require filtration and drugs included in the 2012 table were reviewed for accuracy. Readers are urged to review national standards of practice for information about clinical situations that warrant the use of a filter for medication preparation or administration, independent of the drug being given, and the reader should consult the Food and Drug Administration (FDA)-approved prescribing information for the most up-to-date information.     

EEG Power Asymmetry and Functional Connectivity as a Marker of Treatment Effectiveness in DBS Surgery for Depression

Recently, deep brain stimulation (DBS) has been evaluated as an experimental therapy for treatment-resistant depression. Although there have been encouraging results in open-label trials, about half of the patients fail to achieve meaningful benefit. Although progress has been made in understanding the neurobiology of MDD, the ability to characterize differences in brain dynamics between those who do and do not benefit from DBS is lacking. In this study, we investigated EEG resting-state data recorded from 12 patients that have undergone DBS surgery. Of those, six patients were classified as responders to DBS, defined as an improvement of 50% or more on the 17-item Hamilton Rating Scale for Depression (HAMD-17). We compared hemispheric frontal theta and parietal alpha power asymmetry and synchronization asymmetry between responders and non-responders. Hemispheric power asymmetry showed statistically significant differences between responders and non-responders with healthy controls showing an asymmetry similar to responders but opposite to non-responders. This asymmetry was characterized by an increase in frontal theta in the right hemisphere relative to the left combined with an increase in parietal alpha in the left hemisphere relative to the right in non-responders compared with responders. Hemispheric mean synchronization asymmetry showed a statistically significant difference between responders and non-responders in the theta band, with healthy controls showing an asymmetry similar to responders but opposite to non-responders. This asymmetry resulted from an increase in frontal synchronization in the right hemisphere relative to the left combined with an increase in parietal synchronization in the left hemisphere relative to the right in non-responders compared with responders. Connectivity diagrams revealed long-range differences in frontal/central-parietal connectivity between the two groups in the theta band. This pattern was observed irrespective of whether EEG data were collected with active DBS or with the DBS stimulation turned off, suggesting stable functional and possibly structural modifications that may be attributed to plasticity.