Clozapine in Treatment-Resistant Schizophrenia (TRS): improving access and utilisation

Schizophrenia is the most severe mental illness affecting humans. When the illness does not respond to treatment, it is even more devastating. When a patient fails to respond to two adequate, consecutive antipsychotic treatments, the illness is termed treatment-refractory schizophrenia (TRS). Clozapine is the only licensed and recognised effective treatment in TRS. Interestingly, rather than its current position as a third-line treatment, there are rather robust and convincing arguments for clozapine to be used as a second line. Sadly, in clinical practice there is widespread underuse of clozapine, with significant delays before it is prescribed in individuals with TRS, being relegated to the fifth or sixth line. Instead, non-evidence-based use of high-dose antipsychotics and the use of antipsychotics in combination is common practice, contributing to even longer delays. This is a compilation of 33 of my publications and public works (PWs) spanning over two decades, from 1999 to 2021. In these, I explore why clozapine is underused, when it should be used and how it should be used, employing different methodologies. This is a combination of my reviews of the literature and my practical recommendations on how to overcome difficulties in specific situations using case reports and case series. I have collaborated with colleagues from a wide variety of disciplines including psychiatrists, pharmacologists, cardiologists, haematologists and data experts to advance knowledge in the management of TRS through these works. I have investigated various databases and been involved in the design and conduct of randomised controlled trials in schizophrenia. My work has demonstrated that in the United Kingdom and probably in most other countries, significant variation exists in the rate of clozapine prescribing in patients with TRS. There is thus inequity in patient access to the most effective treatment in refractory schizophrenia. This has an enormous impact on patients and families and may be the difference between long-term institutional care and fulfilling, independent living in the community with freedom and liberty. The delay and underutilisation of clozapine are centred around four principal factors. These are related to the drug itself, factors that relate to the patient, clinician-related factors and finally, those that pertain to licensing and regulatory control of the drug. Clozapine is a life-prolonging drug, and concerted efforts to overcome these well-recognised barriers would go a long way in improving outcomes in patients with TRS. I believe that long-term solutions to the underuse of clozapine lie in education. Clinicians treating patients with schizophrenia need to identify patients with TRS as quickly as possible. Health systems to educate, support and encourage clinicians would provide much-needed confidence in evaluating risks and benefit to increase clozapine uptake. The stringent regulatory controls of clozapine should be thoroughly examined. The United States Food and Drugs Administration (FDA) has gone some way by lowering the haematological threshold for clozapine continuation, but more needs to be done. How can we be confident of overcoming all these seemingly impossible barriers? The answer, I believe, is in developing a national clozapine strategy. The United Kingdom is the centre of research in psychopharmacology. It houses the world-renowned Institute of Psychiatry, Psychology and Neurosciences (IoPPN) with expertise in the management of schizophrenia. A comprehensive national strategy that identifies all the barriers and a systematic approach to addressing the multifaceted problem would address these issues. This approach is not new. It has been successfully applied in countries such as the Netherlands. My PWs have shown that we can not only overcome these barriers, but substantially increase clozapine uptake. The negative prognostic implications of delay and underuse of clozapine are now becoming glaringly apparent. The outcome for patients where clozapine use is substantially delayed is not as good as in patients where it is initiated as soon as treatment refractoriness is ascertained. When we can fully utilise clozapine in patients with TRS, then we can turn our attention to the 40-50% of patients who have less than satisfactory response to clozapine, or those patients deemed as ultra treatment refractory

Analysis of volatile aroma-active compounds from a headspace of a novel whiskey glass

In the literature part of this thesis the human olfactory sense is explored. Also, individual differences in the sense of smell are studied. Since the study focuses on whiskey the anesthetic effects of ethanol on the olfactory system are explored. The different drinking vessels commonly used with whiskey are introduced and reviewed. A novel whiskey glass was studied for its aroma enhancing effects. The glass was designed to lessen the effect of ethanol anesthesia while nosing a whiskey from the glass. A method for headspace solid-phase microextraction (HS-SPME) was developed which adsorbed volatile compounds from the whiskey glass. The HS-SPME method developed was used to analyze whiskey volatile aroma-active compounds. The compounds were identified and quantitated using gas chromatography-flame-ionization detector (GC-FID). For comparison a whiskey sample is quantitated by direct injection and analyzed using gas chromatography-mass spectrometry (GC-MS). Ethanol evaporation experiments were conducted to verify the working principle of the novel whiskey glass. Gas chromatography-olfactometry (GC-O) was used to recognize that the aroma-active compounds of whiskey extracted from the novel glass can be perceived. The HS-SPME method from the whiskey glass was developed to simulate the natural whiskey nosing conditions to ensure relevant results. Several matters regarding the HS-SPME method were considered. These included duration, timing, closed or open headspace and temperature. With the developed method whiskey odorants known to be in the whiskey sample could be identified. Quantitation of these odorants was more challenging and subsequent analyses showed variation in quantities. GC-O also did not perfectly correlate with quantitation’s indicating that some odor-active compounds were under the detection limit

Whiskey in Early America

Following the American Revolution (1775-1781), Americans turned to whiskey as their spirit of choice simply because it was readily available. Whiskey would shape the identity of the early republic after the Whiskey Rebellion (1791-1794) and set the precedent for frontier insurrection and the authority of the federal government. Whiskey became a crucial contributor to the budding economy of early America and the establishment of distilleries and the ease of distribution of the drink opened up the development of the West. Whiskey became so prolific in the first few decades of the United States that even today, it remains a significant piece of the American identity

The Spirit Is Willing: A Proposal for American Single Malt Whiskey

Over the past twenty-five years, small, independent American distilleries have carved out a new niche in the United States liquor market: craft single malt whiskey. Inspired by the success of single malt Scotch and other single malts, American craft distillers are now fighting for their own shelf behind the bar and in the liquor store aisle. In 2018, a cadre of these distillers petitioned the U.S. Treasury Department’s Alcohol and Tobacco Tax and Trade Bureau to formally recognize a new category of whiskey in the Code of Federal Regulations: American Single Malt Whiskey. For purposes of consumer protection, the Treasury Department historically has regulated the production and sales of whiskey in America. Whiskey distillation and bottling is a long and complicated process for distillers who do not take shortcuts. This Note will consider the proposal proffered by the American Single Malt Whiskey Commission. It will then suggest that the proposal is doctrinally sound, beneficial from a policy standpoint, and comports with existing regulations and precedent. Finally, this Note will conclude by speculating as to the likely success of the American Single Malt Whiskey proposal

Methods for Mass Data Acquisition of Whiskey Webs.

Whiskey webs are a recently discovered phenomenon in which the monolayer collapse during evaporation of diluted American whiskey results in self-assembled, web-like structures. It was found that the pattern of weblike structures were unique between different American whiskey products. It is desirable to use these unique patterns as a “fingerprint” which can be used to identify whiskeys, their chemical constituents, and perhaps even counterfeits. In pursuit of identifying whiskey products based on their web pattern, it is necessary to have a large database of samples imaged for each product. The device discussed herein is the realization of an apparatus capable of automating the droplet deposition and imaging of whiskey webs. The apparatus was shown to produce droplets with a smaller volumetric deviation than traditional methods. The apparatus will standardize the droplet deposition procedure and serve as the foundation for statistical studies of whiskey web uniqueness and chemical characterization

Exploring the distilled realms: A study on whiskey and the travellers’ motivations

The study explores the impact of cultural alcoholic beverages, specifically whiskey, on travel motivations. Results from a quantitative research method indicate that both core cultural products and core whiskey products significantly influence the intention to participate in whiskey tourism. The findings suggest that promoting a destination’s reputation as a producer of high-quality cultural alcoholic beverages can enhance its appeal as a tourist destination, and whiskey as a cultural product can motivate tourism.info:eu-repo/semantics/publishedVersio

Whiskey tax of 1791 and the consequent insurrection: A Wicked and happy tumult

This paper examines the development of the Whiskey Tax of 1791 and its criticality in the funding of early federal government debt and operations. By considering some of the provisions of the tax and the collection and enforcement procedures, the financial and social impacts of the Whiskey Tax are clarified. Civil disobedience in resisting the tax and the Whiskey Rebellion of 1794 are explored in that context. Whether the Whiskey Tax effectively served as the first income tax is considered. Images of original record documents are included

Surface Water Geochemical Characteristics near Historical Distillery Locations in Tennessee and Kentucky

Abstract Kentucky and Tennessee has been the primary region in which whiskey has been produced in the United States for the last 200+ years. The locations of Kentucky and Tennessee whiskey distilleries in the pre-industrial era appear to be constrained by the geochemistry of natural waters, stratigraphy, geomorphology, and the average ambient temperatures of fermentation. Distilleries are located near first-order streams where the groundwater surfaces, indicating there was little to no manipulation of these local water sources used in the distilling process during pre-industrial America. These groundwater sources flow through heavily dominated limestone and/or Mg-rich limestone (dolostone), adjusting the geochemistry of the first-order streams creating an optimal Ca-Mg-Fe concentration ratio to create high quality ‘tasting’ whiskey. Collection of water samples in these areas suggest that Kentucky and Tennessee both hold ideal physiographic and hydrologic terrains, as well as the naturally occurring ideal Ca-Mg-Fe concentration ratios in the waters to create high quality ‘tasting’ whiskey. The question of why most American whiskey distilleries has endured prior to the industrial revolution are confined to a small region of Kentucky and Tennessee. No further areas of the southern U.S. with suitable climates or geochemistry for whiskey feedstock productions will be discussed