Long-Term Ketamine Self-Injections in Major Depressive Disorder: Focus on Tolerance in Ketamine’s Antidepressant Response and the Development of Ketamine Addiction

Abstract

Sub-anaesthetic ketamine is of special interest for depression research due to its rapid and potent but short-lived antidepressant response (after-effect). The presented case is the first one in the literature which deals in detail with the transfer from ketamine’s antidepressant action to ketamine addiction. A 50-year-old anaesthetic nurse, who had never been treated with antidepressants before, started with self-injecting ketamine racemate 50 mg IM once a week to cope with her major depression. She continuously stole ketamine from hospital stocks. Due to a gradually developing tolerance to ketamine’s antidepressant action, she stepwise increased dose and frequency of ketamine self-injections up to daily 2 g IM (three-fold her anaesthetic dose) over six months. This was accompanied by the development of ketamine addiction, loss of consciousness, dissociative immobility, and amnesia. Inpatient detoxification treatment was characterized by a strong craving for ketamine and, later on, by the occurrence of a severe depressive episode remitting on venlafaxine. A 14-week follow-up documented a normal condition without any ketamine sequelae, such as craving, psychosis, depression, or cognitive abnormalities. Thus, awareness of ketamine addiction potential, even in patients who received ketamine for antidepressant purposes, is important.     

The Role of Companionship and Conflict in Perceptions of a Friend’s Heavy Alcohol and Marijuana Use

Individuals have been found to “project” their own substance use onto perceptions of their friends’ substance use. This study explores whether companionship and conflict relate to incorrect perceptions of a friend’s heavy alcohol and marijuana use after controlling for the behavior of the respondent and friend. Mixed models demonstrate that having higher levels of companionship, but not conflict, with a friend result in significantly higher perceptual levels of the friend’s heavy alcohol and marijuana use. While beneficial for the friendship, higher levels of companionship may result in a person overestimating the heavy alcohol and marijuana use of a friend.     

Alcohol Use Disorder Identification Test (AUDIT): What Does It Screen? Performance of the AUDIT against Four Different Criteria in a Swedish Population Sample

The purpose of this article was to examine the kinds of alcohol use disorder the AUDIT most accurately screens for since the literature is inconsistent in the use of the AUDIT. Sometimes it is viewed as a measure of hazardous or harmful drinking and sometimes as a measure of dependence. The performance of its subsets (consumption items, AUDIT-C; and problem items, AUDIT-P) and of the full AUDIT (AUDIT-10) was tested against four criteria: high-volume drinking, alcohol-related social problems, alcohol-related health problems, and alcohol dependence. A general population sample of 600 Swedish subjects was interviewed during the winter 2000–01. The results document that, at the recommended cutoff score of 8+, the AUDIT-10 performed well against all four criteria, even if less well against the alcohol-related health problems. The AUDIT-C also performed well against all the problem criteria, showing high areas under the ROC curve, even though significantly lower than the full scale. When measuring high-volume drinking, the AUDIT-C outperformed the full instrument. Scoring at least 1 on the AUDIT-P improved sensitivity of the instrument when screening for social problems and dependence and made it a satisfactory measure of health problems. It is suggested that, when using the full AUDIT to screen for problems more severe than high-volume drinking, the criterion of scoring at least 1 on the AUDIT-P should be applied in combination with a cutoff score on the AUDIT-C.     

Developing an Assessment Process for a Master’s of Science Degree in a Pharmaceutical Sciences Program

Objective. To develop a program-level assessment process for a master’s of science degree in a pharmaceutical sciences (MSPS) program.Design. Program-level goals were created and mapped to course learning objectives. Embedded assessment tools were created by each course director and used to gather information related to program-level goals. Initial assessment iterations involved a subset of offered courses, and course directors met with the department assessment committee to review the quality of the assessment tools as well as the data collected with them. Insights from these discussions were used to improve the process. When all courses were used for collecting program-level assessment data, a modified system of guided reflection was used to reduce demands on committee members.Assessment. The first two iterations of collecting program-level assessment revealed problems with both the assessment tools and the program goals themselves. Course directors were inconsistent in the Bloom’s Taxonomy level at which they assessed student achievement of program goals. Moreover, inappropriate mapping of program goals to course learning objectives were identified. These issues led to unreliable measures of how well students were doing with regard to program-level goals. Peer discussions between course directors and the assessment committee led to modification of program goals as well as improved assessment data collection tools.Conclusion. By starting with a subset of courses and using course-embedded assessment tools, a program-level assessment process was created with little difficulty. Involving all faculty members and avoiding comparisons between courses made obtaining faculty buy-in easier. Peer discussion often resulted in consensus on how to improve assessment tools.     

Suicidality in Offspring of Men with Substance Use Disorder: Is There a Common Liability?

SUMMARY

Suicide is the outcome of a discrete behavioral act which may precede or emerge consequent to a substance use disorder (SUD). A question that has yet to be empirically addressed pertains to the extent to which SUD and suicide have a common liability. The results reported herein indicate that psychological dysregulation in childhood is a risk factor for SUD but not suicidality. Offspring of men with SUD do, however, report a higher rate of suicidal ideation and attempts compared to offspring of psychiatrically normal men. These findings indicate that the risk for suicide and SUD do not completely map to each other but that there may be as yet unidentified factors which are associated with both outcomes.     

Does a History of Violence Influence Treatment,Self-Help,and 1-Year Outcomes in Substance Use Disorder Patients?

ABSTRACT

Rates of violence perpetration are high among patients with substance use disorder, but the impact of violence on substance use disorder treatment outcomes has received little attention. Patients with (n = 155) or without (n = 190) a history of difficulty controlling violent behavior were interviewed at entry to substance use disorder treatment and 1 year later. Substance use disorder severity, amount of treatment, and extent of participation in 12-step self-help groups were assessed to examine potential differences in treatment outcomes between violent and non-violent patients. After adjusting for baseline differences, no differences in substance use disorder severity were found at 1 year. However, over the year, violent patients received more treatment and participated more in 12-step groups compared to non-violent patients. In addition, violent patients benefited more from 12-step group participation than non-violent patients did. Referral to 12-step self-help groups may enhance the likelihood of recovery from a substance use disorder for patients with a history of violence.     

“[Drinking is] Like a Rule That You Can't Break”: Perceived Barriers and Facilitators to Reduce Alcohol Use and Improve Antiretroviral Treatment Adherence among People Living with HIV and Alcohol Use Disorder in Vietnam

Background: Alcohol use, a highly normative behavior in Vietnam that is associated with high rates of HIV infection and lower antiretroviral treatment (ART) adherence, has been largely overlooked by HIV prevention efforts. Objectives: Using the risk environment framework, this qualitative study aims to explore the perceived microenvironmental (community-level) and endogenous (individual-level) barriers and facilitators to alcohol reduction among people living with HIV (PLHIV) with alcohol use disorders (AUDs) in Vietnam. Methods: From June-July 2014, semi-structured interviews were conducted with thirty PLHIV (18 men; 12 women) recruited from an outpatient ART clinic in Thai Nguyen province, Vietnam. All participants had scores of ≥8 on the Alcohol Use Disorders Identification Test and ten of the 30 participants were currently using injection drugs. Interviews were transcribed, translated, and analyzed to identify perceived barriers and facilitators to alcohol reduction. Results: Most participants reported a spike in alcohol consumption at the time of HIV diagnosis. Most perceived barriers existed at the microenvironmental level, including perceived inability to refuse alcohol in the context of community-level social norms and lack of alcohol treatment programs. Two commonly mentioned endogenous barriers were compensatory behaviors when reducing injection drug use and using alcohol as a coping strategy for HIV-related sadness. Those who were able to successfully reduce alcohol use and adhere to ART reported having social support to buffer community-level social pressure and cope with sadness. Conclusions: It may be effective to introduce targeted alcohol reduction interventions in health care centers to address individual risk practices and microenvironmental social norms.     

Improving the Diagnosis and Treatment of CRPS: Insights from a Clinical Immunologist’s Personal Experience with an Underrecognized Neuroinflammatory Disorder

Complex regional pain syndrome is a neuroinflammatory condition associated with overactive glial cells that can be challenging to diagnose and treat. Early recognition and treatment are thought to be critical for good outcomes, yet many patients experience a delay in diagnosis and have difficulty accessing expert medical care. While there are no universally effective treatments, there are several promising new therapies, but these are not widely available. Some of the specific barriers to diagnosis and treatment are reviewed, with suggestions as to how they might be eliminated, leading to better care for all patients with CRPS.     

Efficacy of a Therapeutic Vaccine Using Mutated β-amyloid Sensitized Dendritic Cells in Alzheimer’s Mice

Despite FDA suspension of Elan's AN-1792 amyloid beta (Aβ) vaccine in phase IIb clinical trials, the implications of this study are the guiding principles for contemporary anti-Aβ immunotherapy against Alzheimer's disease (AD). AN-1792 showed promising results with regards to Aβ clearance and cognitive function improvement, but also exhibited an increased risk of Th1 mediated meningoencephalitis. As such, vaccine development has continued with an emphasis on eliciting a notable anti-Aβ antibody titer, while avoiding the unwanted Th1 pro-inflammatory response. Previously, we published the first report of an Aβ sensitized dendritic cell vaccine as a therapeutic treatment for AD in BALB/c mice. Our vaccine elicited an anti-Aβ titer, with indications that a Th1 response was not present. This study is the first to investigate the efficacy and safety of our dendritic cell vaccine for the prevention of AD in transgenic mouse models (PDAPP) for AD. We also used Immunohistochemistry to characterize the involvement of LXR, ABCA1, and CD45 in order to gain insight into the potential mechanisms through which this vaccine may provide benefit. The results indicate that (1) the use of mutant Aβ1-42 sensitized dendritic cell vaccine results in durable antibody production, (2) the vaccine provides significant benefits with regards to cognitive function without the global (Th1) inflammation seen in prior Aβ vaccines, (3) histological studies showed an overall decrease in Aβ burden, with an increase in LXR, ABCA1, and CD45, and (4) the beneficial results of our DC vaccine may be due to the LXR/ABCA1 pathway. In the future, mutant Aβ sensitized dendritic cell vaccines could be an efficacious and safe method for the prevention or treatment of AD that circumvents problems associated with traditional anti-Aβ vaccines.     

Pharmacotherapy for the treatment of depression in patients with alzheimer’s disease: a treatment-resistant depressive disorder

Introduction: Pharmacotherapy for the treatment of depressive disorders in Alzheimer’s Disease (AD) represents a clinical challenge. pharmacological options are often attempted after a period of watchful waiting (8–12 weeks). monoaminergic antidepressant drugs have shown only modest or null clinical benefits, maybe because the etiology of depressive symptoms in ad patients is fundamentally different from that of nondemented subjects.

Areas covered: The following article looks at the selective serotonin reuptake inhibitor sertraline, which is one of the most frequently studied antidepressant medications in randomized controlled trials (RCTs). It also discusses many other pharmacological approaches that have proven to be inadequate (antipsychotics, acetylcholinesterase inhibitors, anticonvulsants, hormone replacement therapy) and new drug classes (mainly affecting glutamate transmission) that are being studied for treating depression in AD. It also gives discussion to the phase II RCT on the alternative drug S47445 and the potential effect on cognition of the multimodal antidepressant vortioxetine in older depressed patients. Finally, it discusses the N-methyl-D-aspartate antagonist ketamine.

Expert opinion: The present RCT methodologies are too disparate to draw firm conclusions. Future studies are required to identify effective and multimodal pharmacological treatments that efficiently treat depression in AD. Genotyping may boost antidepressant treatment success.     

What’s in a drop? Optimizing strategies for administration of drugs in pediatrics

Accurate administration of drugs is an essential part of pharmacotherapy in children. Small differences in the amount of drugs administered, might evoke different clinical effects. This is especially of concern in drugs with a narrow therapeutic index. Guided by a case that was observed in pediatrics, some practical recommendations for the administration of oral drops in children are described.     

Neuroprotection by marine-derived compound, 11-dehydrosinulariolide, in an in vitro Parkinson’s model: a promising candidate for the treatment of Parkinson’s disease

Parkinson's disease (PD) is a neurodegenerative disease characterized by tremor, rigidity, bradykinesia, and gait impairment. So far, very few pharmacological agents have been isolated or developed that effectively inhibit the progression of PD. However, several studies have demonstrated that inflammatory processes play critical roles in PD. Therefore, anti-inflammatory agents may suppress disease progression in PD. 11-Dehydrosinulariolide was isolated from cultured soft corals. The anti-inflammatory effect of this molecule has been observed through suppression of the expression of two main pro-inflammatory proteins: inducible nitric oxide synthase and cyclooxygenase-2, in lipopolysaccharide-stimulated macrophage cells. We also found that 11-dehydrosinulariolide significantly reduced 6-hydroxydopamine (6-OHDA)-induced cytotoxicity and apoptosis in a human neuroblastoma cell line (SH-SY5Y). The pharmacological activity of this compound has been studied, and it is associated with the inhibition of 6-OHDA-induced activation of caspase-3 and translocation of nuclear factor kappa B. 11-Dehydrosinulariolide increased the activation of survival-signaling phospho-Akt but not phospho-ERK. The neuroprotective effect of 11-dehydrosinulariolide was assessed here using 6-OHDA-treated SH-SY5Y cells, wherein neuroprotection is mediated through regulation of phosphatidylinositol 3-kinase (PI3K). Furthermore, 11-dehydrosinulariolide caused a significant decrease in caspase-3/7 activity in comparison to the 6-OHDA-treated group, indicating that 11-dehydrosinulariolide has neuroprotective properties. We conclude that 11-dehydrosinulariolide is a promising candidate for the treatment of Parkinson's disease through its anti-apoptotic and anti-inflammatory action via PI3K signaling.     

Compounds for imaging amyloid-β deposits in an Alzheimer’s brain: a patent review

Introduction: β-amyloid (Aβ) plaques in the brain are regarded as a hallmark of Alzheimer’s disease (AD), and the imaging of Aβ is a critical step for early diagnosis. Extensive research has been done to develop probes for targeting Aβ with available imaging modalities.

Areas covered: In this review, the authors give an overview of published patents and papers about the discovery and development of compounds possessing potential utilization in imaging Aβ for the diagnosis of AD. SciFinder is the main electronic database for patent study in this review.

Expert opinion: Despite achievements in Aβ imaging, there is still a need to develop innovative compounds with selectivity and high affinity to Aβ. Positron emission tomography imaging agents will still be the trend in the field in the short term. Due to the low costs for single-photon emission computed tomography (SPECT) and the excellent nuclear properties of ^99mTc, substantial research should be conducted on the development of the probes for SPECT. Refining the current imaging techniques and in the meantime developing new efficient imaging multimodality and compounds would be a promising approach to imaging Aβ.     

Istradefylline for the treatment of Parkinson’s disease: is it a promising strategy?

ABSTRACT

Introduction: Istradefylline (ISD) is a new drug developed for the treatment of Parkinson’s disease (PD). It is an adenosine receptor A_2A antagonists that will represent an important option for patients with advanced PD where it has been demonstrated efficacy in decreasing daily OFF time and is well tolerated. ISD has been marketed in Japan since May 2013.

Areas covered: The objective of this review is to summarize evidences emerged from clinical studies that have demonstrated the efficacy of ISD in advanced parkinsonian patients. It will then focus on the potential role in treating non-motor symptoms (NMS) and cognitive decline, which heavily affect quality of life for PD patients. Its putative role as neuroprotective agent will also be discussed.

Expert opinion: ISD might represent an alternative option for patients with advanced PD. The reduction of OFF time highlighted in pivotal trials is comparable to that obtained with different levodopa adjunct therapies. The low profile of side effects makes ISD a more suitable drug for advanced patients whose illness is complicated by depression or cognitive impairment. Future studies are warranted to investigate the possible effects of this drug to delay the occurrence of dyskinesia and to impact significantly on NMS.     

Developments with multi-target drugs for Alzheimer’s disease: an overview of the current discovery approaches

ABSTRACT

Introduction: Alzheimer’s disease (AD), the most common type of dementia among older adults, is a chronic neurodegenerative pathology that causes a progressive loss of cognitive functioning with a decline of rational skills. It is well known that AD is multifactorial, so there are many different pharmacological targets that can be pursued.

Areas covered: The authors highlight the strategic value of privileged scaffolds in a multi-target lead compound generation against AD, exploring the concept of multi-target design, with a special emphasis on hybrid compounds. Hence, the most promising building blocks for designing and synthesizing hybrid anti-AD drugs are shown, while also presenting the more advanced hybrid compounds.

Expert opinion: The available therapeutic arsenal for AD, designed under the traditional paradigm of ‘one-drug/one target/one-disease’, is based on the inhibition of brain acetylcholinesterase (AChE) to increase acetylcholine (ACh) levels. However, this classical approach has not been sufficiently effective when used to treat any multifactor-depending pathology (cancer, diabetes or AD). The multi-target drug concept has been quickly adopted by medicinal chemists. The basic research developments reported in recent years are a solid foundation that will pave the way for the construction of future AD therapeutics.     

Abnormal hippocampal neurogenesis in Parkinson’s disease: relevance to a new therapeutic target for depression with Parkinson’s disease

Parkinson’s disease (PD) is a common progressive neurodegenerative disorder characterized by motor dysfunction, including bradykinesia, tremor, rigidity, and postural instability. Recent clinical findings recognize PD as a complex disease with diverse neuropsychiatric complications. Depression is the most frequent non-motor psychiatric symptom experienced in PD, and it is associated with poor quality of life. While the pathophysiology of PD-associated depression is not directly related to neurodegenerative processes in the substantia nigra, underlying mechanisms remain unclear and there are few symptomatic treatments. Altered adult hippocampal neurogenesis is considered crucial for the development and treatment of depression. In genetic animal models and human postmortem studies of PD, severely impaired adult neurogenesis has been observed, with patients showing hippocampal atrophy and disrupted hippocampal neurogenesis. Because adult newborn neurons appear to exert various functions, which relate to non-motor symptoms observed in PD, there might be a close correlation between malformation of newborn neurons in the adult hippocampus and depressive symptoms. Here, we discuss current concepts regarding impaired hippocampal neurogenesis and non-motor symptoms of PD, and review PD-associated pathophysiological factors regulating neurogenesis, including inflammatory signaling and autophagy. We present a novel framework for targeting adult hippocampal neurogenesis, which could provide a promising treatment for PD-associated depression.     

Efficacy and safety of adalimumab for the Crohn’s disease: a systematic review and meta-analysis of published randomized placebo-controlled trials

Purpose

The aim of this study was to evaluate the efficacy and safety of adalimumab (ADA) for Crohn’s disease.

Methods

Electronic databases, including PubMed, Embase, the Cochrane Library, and the Science Citation Index, were searched to retrieve relevant trials. We estimated pooled estimates of the odds ratio (OR) and relevant 95 % confidence interval (CI) using fixed effects model or random effects model as appropriate.

Results

Six randomized placebo-controlled studies met the selection criteria. Short-term clinical response/remission and long-term remission were better in the ADA groups than in the control groups (P?<?0.05), both in anti-TNF-naive patients and in subjects who lost their response and/or became intolerant to infliximab (IFX). And ADA was also effective for patients who were previously treated with IFX, and its efficacy in infliximab-exposed patients was probably less than in infliximab-naive patients. In patients with active Crohn’s disease (CD), ADA therapy was more effective than placebo for obtaining complete fistula closure. In comparison with placebo, ADA does not increase the risk of serious adverse events.

Conclusions

ADA appears to be effective in achieving short-term clinical response/remission, long-term remission, and complete fistula healing in CD, including patients not manageable with IFX, and appears to have a favorable safety profile. A longer duration of follow-up and a larger number of patients are required to better assess the safety profile of ADA in CD.     

Evaluation of rotigotine transdermal patch for the treatment of depressive symptoms in patients with Parkinson’s disease

Objective: To evaluate the dopamine receptor agonist, rotigotine, for improving depressive symptoms in patients with Parkinson’s disease (PD).

Methods: Patients were randomized 1:1 to rotigotine or placebo, titrated for ≤7 weeks, and maintained at optimal/maximum dose for 8-weeks. Primary efficacy variable: 17- item Hamilton Depression Rating Scale (HAM-D 17) total score change from baseline to end-of-maintenance. Secondary variables: changes in Beck Depression Inventory-II, Unified Parkinson’s Disease Rating Scale (UPDRS) II (activities of daily living [ADL]) and III (motor) subscores, UPDRS II+III total, patient-rated Apathy Scale (AS), and Snaith-Hamilton Pleasure Scale.

Results: Of 380 patients randomized, 149/184 (81.0%) rotigotine-treated and 164/196 (83.7%) placebo-treated patients completed the study. Patients: mean (±SD) age 65.2 (±8.5) years; time since PD-diagnosis 2.74 (±3.08) years; 42.6% male. The treatment difference (LS mean [95% CI]) in change from baseline HAM-D 17 was ?1.12 (?2.56, 0.33; p = 0.1286). UPDRS II, III, II+III and AS scores improved numerically with rotigotine versus placebo. Common adverse events with higher incidence with rotigotine: nausea, application/instillation site reactions, vomiting, and pruritus. Forty-one (10.8%) patients discontinued owing to adverse events (25 rotigotine/16 placebo).

Conclusions: No statistically significant improvement in depressive symptoms were observed with rotigotine versus placebo. ADL, motor function, and patient-rated apathy improved numerically.

ClinicalTrials.gov: NCT01523301