Rapid-acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective.

Major depressive disorder (MDD) is one of the most disabling psychiatric disorders. Approximately one-third of the patients with MDD are treatment resistant to the current antidepressants. There is also a significant therapeutic time lag of weeks to months. Furthermore, depression in patients with bipolar disorder (BD) is typically poorly responsive to antidepressants. Therefore, there exists an unmet medical need for rapidly acting antidepressants with beneficial effects in treatment-resistant patients with MDD or BD. Accumulating evidence suggests that the N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine produces rapid and sustained antidepressant effects in treatment-resistant patients with MDD or BD. Ketamine is a racemic mixture comprising equal parts of (R)-ketamine (or arketamine) and (S)-ketamine (or esketamine). Because (S)-ketamine has higher affinity for NMDAR than (R)-ketamine, esketamine was developed as an antidepressant. On 5 March 2019, esketamine nasal spray was approved by the US Food and Drug Administration. However, preclinical data suggest that (R)-ketamine exerts greater potency and longer-lasting antidepressant effects than (S)-ketamine in animal models of depression and that (R)-ketamine has less detrimental side-effects than (R,S)-ketamine or (S)-ketamine. In this article, the author reviews the historical overview of the antidepressant actions of enantiomers of ketamine and its major metabolites norketamine and hydroxynorketamine. Furthermore, the author discusses the other potential rapid-acting antidepressant candidates (i.e., NMDAR antagonists and modulators, low-voltage-sensitive T-type calcium channel inhibitor, potassium channel Kir4.1 inhibitor, negative modulators of γ-aminobutyric acid, and type A [GABAA ] receptors) to compare them with ketamine. Moreover, the molecular and cellular mechanisms of ketamine's antidepressant effects are discussed.

[Research on Depression in the GDR - Historical Lines of Development and Therapeutic Approaches]. / Depressionsforschung in der DDR - historische Entwicklungslinien und Therapieansätze.

BACKGROUND: Historical research has raised the issue of whether GDR psychiatry was isolated from Western influences to such an extent that an autonomous East German psychiatry developed. Taking a chronological approach and being based on a clearly defined range of topics, the objective of this paper is to identify specific contributions made by GDR psychiatry to academic research as well as the degree of its international orientation by focusing on the treatment and research on depression. METHODS: We have performed a systematic review of the East German psychiatric journal "Psychiatrie, Neurologie und medizinische Psychologie" and a screening of all psychiatric textbooks that appeared in the GDR. RESULTS: Although East German psychiatry was oriented towards Soviet as well as Western developments, some internationally used therapeutic or conceptual innovations reached East German clinics only with some delay. Yet, East German psychiatrists have also contributed their own, independent nosological and therapeutic concepts to research on depression. Pivotal figures included, among others, R. Lemke (Jena), D. Müller-Hegemann (Leipzig) or K. Leonhard (Berlin). CONCLUSION: With regard to research on depression one cannot truly speak of an autonomous East German psychiatry. Developments in East and West were largely running in parallel.

[Drug treatments, from chlorpromazine to new molecules]. / Traitements médicamenteux, de la chlorpromazine aux nouvelles molécules.

The history of drug treatments, and particularly the discovery of certain molecules, led toan evolution in psychiatric practices. The discovery of the therapeutic properties of chlorpromazine in 1952 by Jean Delay and Pierre Deniker revolutionised the relational process between patients and caregivers.The perspectives are encouraging, notably in the areas of schizophrenia and mood disorders.

Cade's identification of lithium for manic-depressive illness--the prospector who found a gold nugget.

John Cade's identification of lithium as a treatment of manic-depressive illness has been judged as a landmark biomedical advance and as an initiator of modern psychopharmacology. His personal background, interests, character, experiences, and key observational skills are sketched to provide the background and logic for his discovery and to argue against his simple self-description as a clinician administrator. The Cade story illustrates the potential strengths of clinical research whereby the clinician observes "signals," formulates hypotheses and explanations, and then pursues or encourages their validity and application. The suggestion that Cade simply "rediscovered lithium" is rejected.

Antidepressants and advertising: psychopharmaceuticals in crisis.

As the efficacy and science of psychopharmaceuticals has become increasingly uncertain, marketing of these drugs to both physicians and consumers continues to a central part of a multi-billion dollar per year industry in the United States. We explore how such drug marketing portrays idealized scientific relationships between psychopharmaceuticals and depression; how multiple stakeholders, including scientists, regulatory agencies, and patient advocacy groups, negotiate neurobiological explanations of mental illness; and how the placebo effect has become a critical issue in these debates, including the possible role of drug advertising to influence the placebo effect directly. We argue that if and how antidepressants "work" is not a straightforward objective question, but rather a larger social contest involving scientific debate, the political history of the pharmaceutical industry, cultural discourses surrounding the role of drugs in society, and the interpretive flexibility of personal experience.

'On periodical depressions and their pathogenesis' by Carl Lange (1886).

Carl Lange was the founding father of neurology in Denmark, authoring several pioneering works within this field; however, these remained largely unknown internationally as he did not have them translated into a major language. He became a pioneer of psychophysiology with his contribution to the so-called James-Lange theory of emotion. His treatise on'periodical depressions' ('the Lange theory of depressions', 1886), is not only an early historical landmark but also a masterly 'modern' description concerning the nosology and nosography of recurrent depressions. Moreover, it is a landmark in the early history of lithium therapy, sadly ignored by Lange's contemporaries, but which little more than half a century later, with Cade's rediscovery of lithium's therapeutic effect in mood disorders in 1949, ushered in modern psychopharmacology.

Visualizing the evolution of evidence: Cumulative network meta-analyses of new generation antidepressants in the last 40 years.

It is often challenging to present the available evidence in a timely and comprehensible manner. We aimed to visualize the evolution of evidence about antidepressants for depression by conducting cumulative network meta-analyses (NMAs) and to examine whether it could have helped the selection of optimal drugs. We built a Shiny web application that performs and presents cumulative NMAs based on R netmeta. We used a comprehensive dataset of double-blind randomized controlled trials of 21 antidepressants in the acute treatment of major depression. The primary outcomes were efficacy (treatment response) and acceptability (all-cause discontinuation), and treatment effects were summarized via odds ratios. We evaluated the confidence in evidence using the CINeMA (Confidence in Network Meta-Analysis) framework for a series of consecutive NMAs. Users can change several conditions for the analysis, such as the period of synthesis, among the others. We present the league tables and two-dimensional plots that combine efficacy, acceptability and level of confidence in the evidence together, for NMAs conducted in 1990, 1995, 2000, 2005, 2010, and 2016. They reveal that through the past four decades, newly approved drugs often showed initially exaggerated results, which tended to diminish and stabilize after approximately a decade. Over the years, the drugs with relative superiority changed dramatically; but as the evidence network grew larger and better connected, the overall confidence improved. The Shiny app visualizes how evidence evolved over years, emphasizing the need for a careful interpretation of relative effects between drugs, especially for the potentially amplified performance of newly approved drugs. HIGHLIGHTS: Network meta-analysis is considered to be a proper way of demonstrating the available evidence, since it allows comparisons between multiple interventions, and has been proved to be statistically powerful. It is challenging to present the voluminous results of NMA in an efficient and comprehendible manner. Evidence evolution based on the relatively new method NMA has not been investigated yet. The results of NMA should not only include the effects but also the confidence in the evidence, which can help interpret the findings appropriately. Effective use of rapidly developing statistical analysis and presentation tools such as Shiny package in R, may facilitate and simplify the visualization of NMA output. We should stay conservative towards new drugs, as their performance was often shown to be exaggerated initially, and it took time to become stable.

Profitable failure: antidepressant drugs and the triumph of flawed experiments.

Drawing on an analysis of Irving Kirsch and colleagues' controversial 2008 article in "PLoS [Public Library of Science] Magazine" on the efficacy of SSRI antidepressant drugs such as Prozac, I examine flaws within the methodologies of randomized controlled trials (RCTs) that have made it difficult for regulators, clinicians and patients to determine the therapeutic value of this class of drug. I then argue, drawing analogies to work by Pierre Bourdieu and Michael Power, that it is the very limitations of RCTs -- their inadequacies in producing reliable evidence of clinical effects -- that help to strengthen assumptions of their superiority as methodological tools. Finally, I suggest that the case of RCTs helps to explore the question of why failure is often useful in consolidating the authority of those who have presided over that failure, and why systems widely recognized to be ineffective tend to assume greater authority at the very moment when people speak of their malfunction.

A half-century of participant observation in psychiatry. Part III: psychopharmacology. / Pól wieku obserwacji uczestniczacej w psychiatrii. Czesc III. Psychofarmakologia.

The third part of the triptych of my 50-year activity in psychiatry is about psychopharmacology. This way of treatment changed the picture of contemporary psychiatry. The introduction of neuroleptic (antipsychotic) drugs and tricyclic antidepressants in the 1950s resulted in a therapeutic revolution and contributed to the ?medicalization' of psychiatry and its therapeutic similarity to other non-surgical specialties. Adiscovery of prophylactic lithium activity in the1960s initiated the mood-stabilizing drugs.During the last half-century, the most dynamic was the 1990s when most antipsychotic and antidepressant drugs of the so-called new generation were introduced. The twenty-first century marks a debut of next antidepressant and antipsychotic drugs, some of the latter having long-acting injectable preparations. An interesting event was a demonstration of the antidepressant activity of ketamine. My research domain in psychopharmacology was lithium treatment of affective illnesses. Lithium makes the topic of many papers I authored, more than 150 of them are in the PubMed database. Many clinical and research aspects related to lithium administration have been reported as first in Polish literature and some are pioneering in the world. Recently, I wrote the book Lithium - the amazing drug in psychiatry which has also its English version. I have carried much research on antidepressant drugs, pharmacotherapy of treatment-resistant depression, and mood-stabilizing drugs for which I proposed a modern classification. I participated in European projects EUFEST and OPTIMISE on the optimization of using antipsychotic drugs in schizophrenia. I also performed much research on the antidepressant effect of ketamine and electroconvulsive therapy.

Serotonin discovery and stepwise disclosure of 5-HT receptor complexity over four decades. Part II. Some contributions of Manfred Göthert.

About 40% of the papers within the scientific oeuvre of Manfred Göthert (1939-2019) were dedicated to serotonin (5-hydroxytryptamine, 5-HT). He was not only the witness of the gradual definition of the fourteen 5-HT receptor subtypes but also was involved directly by identifying 5-HT1B, 5-HT1D and 5-HT3 receptors. Moreover, he identified presynaptic 5-HT receptors on central and/or peripheral serotoninergic, noradrenergic and/or cholinergic neurones. Two inhibitory (5-HT1B, 5-HT1D) and two facilitatory (5-HT3, 5-HT4) receptors were found, the 5-HT1B receptor representing a possible target for antidepressant drugs. Ten years earlier than electrophysiologists, he identified ligand-gated receptors like the 5-HT3 and the nicotinic acetylcholine (nACh) receptor as targets of halothane. Simultaneously with, but independent of, other authors he found that ethanol allosterically inhibits N-methyl-D-aspartate (NMDA) receptors, which are affected at an even lower concentration than 5-HT3 and nACh receptors. The latter two receptors were shown to be subject to allosteric inhibition also by cannabinoids via a mechanism unrelated to cannabinoid CB1 or CB2 receptors; cannabinoid inhibition of 5-HT3 receptors may represent a new target for the treatment of neuropathic pain.

Drug evaluation and the permissive principle: continuities and contradictions between standards and practices in antidepressant regulation.

Pharmaceuticals are not permitted on to the market unless they are granted regulatory approval. The regulatory process is, therefore, crucial in whether or not a drug is widely prescribed. Regulatory agencies have developed standards of performance that pharmaceuticals are supposed to meet before entering the market. Regulation of technologies is often discussed by reference to the precautionary principle. In contrast, this paper develops the concept of the 'permissive principle' as a way of understanding the departure of regulators' practices from standards of drug efficacy to which regulatory agencies themselves subscribe. By taking a case study of antidepressant regulation in the UK and the USA, the mechanisms of permissive regulatory practices are examined. An STS methodology of both spatial (international) and temporal comparisons of regulatory practices with regulatory standards is employed to identify the nature and extent of the permissive regulation. It is found that the permissive principle was adopted by drug regulators in the UK and the USA, but more so by the former than the latter. Evidently, permissive regulation, which favours the commercial interests of the drug manufacturer, but is contrary to the interests of patients, may penetrate to the heart of regulatory science. On the other hand, permissive regulation of specific drugs should not be regarded as an inevitable result of marketing strategies and concomitant networks deployed by powerful pharmaceutical companies, because the extent of permissive regulation may vary according to the intra-institutional normative commitments of regulators to uphold their technical standards against the commercial interests of the manufacturer. Likely sociological factors that can account for such permissive regulatory practices are 'corporate bias', secrecy and excessive regulatory trust in the pharmaceutical industry in the UK, political expediency and ideological capture in the USA, combined in both countries with some regulatory deference to the clinical autonomy of the psychiatry profession.

Staging Treatment Intensity and Defining Resistant Depression: Historical Overview and Future Directions.

OBJECTIVE: To review existing staging models and definitions of treatment-resistant depression (TRD) and offer future directions within the context of up-to-date evidence. DATA SOURCES: A PubMed search was conducted on February 25, 2018, for articles in English on TRD staging or definition using the following keywords: depressive disorder, treatment-resistant OR treatment resistant depression cross-referenced with staging OR degree OR level OR definition. Relevant cross-references from identified articles were also included. STUDY SELECTION: A total of 18 articles were identified that included a proposed TRD staging model, a proposed TRD definition, empirical work to support a model or definition, or any combination thereof. DATA EXTRACTION: Included articles were summarized in chronological order in terms of the date the TRD staging model (and accompanying TRD definition if applicable) was first proposed. Findings from validation studies pertaining to staging or definition were then synthesized. RESULTS: Five staging models were identified. Strengths identified across staging models include rigorous assessment of adequacy of treatment, differentiation of resistance versus symptom return, assignment of equal weights to different pharmacotherapies, and accounting for augmentation. Future considerations should include differential weighting to specific augmentation agents based on available evidence, added weight to electroconvulsive therapy and ketamine treatments, and the addition of evidence-based psychotherapies. Dichotomous versus continuous approaches to TRD diagnosis were considered, with the latter (beginning with 1 failed trial) best explaining available data from large trials. CONCLUSIONS: The most up-to-date evidence in the literature should guide future research in the definition and staging of TRD.

The creation of the concept of an antidepressant: an historical analysis.

The concept of an "antidepressant" implies a drug that acts in a disease specific way to reverse the neuropathological basis of the symptoms of depression. However, there is little scientific research that could confirm this view. This paper reports an historical study of the emergence of the concept of the antidepressant and the social forces that influenced its adoption. Historical literature documents the increasing importance of the specificity of medical treatments in the 20th century and the increased power that they conferred on medical practitioners. In the case of depression, stimulants were used as treatment from the 1940s. During the 1950s the anti-tuberculous drugs iproniazid and isoniazid started to be portrayed as more specific than stimulants, even though their stimulant effects were well documented. When imipramine was suggested to be effective in depression, it was presented solely as acting in a disease specific way and it was soon referred to as an "antidepressant". The idea that some drugs have a specific action on the underlying basis of depression caught on rapidly and was well established by the 1960s before any evidence was available to support this view. Forces that could have driven the adoption of this view include the psychiatric profession's desire to integrate with general medicine to improve its social status and to move away from the asylum into the community. Physical interventions and drug treatments helped to boost its medical credentials and antidepressant drugs provided a convenient form of medical treatment for community-based distress. They also helped the profession to counter attacks from the antipsychiatry movement. The pharmaceutical industry too helped to establish and disseminate the view of antidepressants as disease specific treatments in order to distinguish them from non-specific drugs. This study raises questions about the view that psychiatry was transformed into a modern medical enterprise in the 1950s and 1960s by the introduction of disease specific drugs.

The conundrum of depression clinical trials: one size does not fit all.

In this paper we review the history of antidepressant (AD) development, since the discovery of imipramine in 1957 to the present day. Through this exploration we will show that the increasing placebo response is likely a red herring and that a higher magnitude of placebo response is not an adequate explanation for AD trials' high failure rates. As a better explanation for their lack of success, we will examine some of the fundamental flaws of AD clinical trials and their origins in historical forces. We focus on underpowering, which occurs as a consequence of unrealistic expectations for AD performance. In addition, we describe the lack of precision in the depression outcome measurements for the past 40 years and show how these measures contrast with those used in clinical trials of other chronic diseases, which use simpler outcome measures. Finally, we describe the role of regulatory agencies in influencing clinical trial design and how the assumption that 'one size fits all' for the past 60 years has led to flawed design of AD clinical trials.

American health care systems and depression: the past, present, and the future.

American medicine has witnessed 3 major periods in this century that have all played key roles in the evolution of today's medical systems, practice, and education. The first of these periods followed the publication of the Flexner report in the early 1900s that was critical of the then current medical education system. The second came with the development of specialties in the 1920s and 1930s, and the third with the growth of HMOs and managed care and with the reemergence of primary care. Mental health practice has also evolved, moving from a specialist-based direct access to a primary care model. Although great strides have been made regarding the treatment of depression, an overwhelming majority of patients are still undertreated. Treatments for the future must focus on programs to improve recognition of depression, reduce stigma, and increase compliance.

History and evolution of the monoamine hypothesis of depression.

The symptoms of depression can be improved by agents that act by various mechanisms to increase synaptic concentrations of monoamines. This finding led to the adoption of the monoamine hypothesis of depression, first put forward over 30 years ago, which proposes that the underlying biological or neuroanatomical basis for depression is a deficiency of central noradrenergic and/or serotonergic systems and that targeting this neuronal lesion with an antidepressant would tend to restore normal function in depressed patients. The hypothesis has enjoyed considerable support, since it attempts to provide a pathophysiologic explanation of the actions of antidepressants. However, in its original form it is clearly inadequate, as it does not provide a complete explanation for the actions of antidepressants, and the pathophysiology of depression itself remains unknown. The hypothesis has evolved over the years to include, for example, adaptive changes in receptors to explain why there should be only a gradual clinical response to antidepressant treatment when the increase in availability of monoamines is rapid. Still, the monoamine hypothesis does not address key issues such as why antidepressants are also effective in other disorders such as panic disorder, obsessive-compulsive disorder, and bulimia, or why all drugs that enhance serotonergic or noradrenergic transmission are not necessarily effective in depression. Despite these limitations, however, it is clear that the development of the monoamine hypothesis has been of great importance in understanding depression and in the development of safe and effective pharmacologic agents for its treatment.