Category: Mental Health

Who was Benedict Morel (1809-1873)?

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Introduction

Bénédict Augustin Morel (22 November 1809 to 30 March 1873) was a French psychiatrist born in Vienna, Austria. He was an influential figure in the field of degeneration theory during the mid-19th century.

Biography

Morel was born in Vienna, Austria in 1809, of French parents. In the aftermath of the War of the Sixth Coalition Morel was abandoned by his parents, and left with the Luxembourgish Abbé Dupont and his servant Marianne, who raised him.

Morel received his education in Paris, and while a student, supplemented his income by teaching English and German classes. In 1839 he earned his medical doctorate, and two years later became an assistant to psychiatrist Jean-Pierre Falret (1794–1870) at the Salpêtrière in Paris.

Morel’s interest in psychiatry was further enhanced in the mid-1840s when he visited several mental institutions throughout Europe. In 1848 he was appointed director of the Asile d’Aliénés de Maréville at Nancy. Here he introduced reforms towards the welfare of the mentally ill, in particular liberalization of restraining practices. At the Maréville asylum he studied people with mental disabilities, researching their family histories and investigating aspects such as poverty and childhood physical illnesses. In 1856 he was appointed director of the mental asylum at Saint-Yon in Rouen.

Morel, influenced by various pre-Darwinian theories of evolution, particularly those that attributed a powerful role to acclimation, saw mental deficiency as the end stage of a process of mental deterioration. In the 1850s, he developed a theory of “degeneration” in regards to mental problems that take place from early life to adulthood. In 1857 he published Traité des dégénérescences physiques, intellectuelles et morales de l’espèce humaine et des causes qui produisent ces variétés maladives, a treatise in which he explains the nature, causes, and indications of human degeneration. Morel looked for answers to mental illness in heredity, although later on he believed that alcohol and drug usage could also be important factors in the course of mental decline.

Démence Précoce

In the first volume of his Études cliniques (1852) Morel used the term démence précoce in passing to describe the characteristics of a subset of young patients, and he employed the phrase more frequently in his textbook Traité des maladies mentales which was published in 1860. Morel used the term in a descriptive sense and not to define a specific and novel diagnostic category. It was applied as a means of setting apart a group of young men and women who had “stupor.” As such their condition was characterised by a certain torpor, enervation, and disorder of the will and was related to the diagnostic category of melancholia. His understanding of dementia was a traditional and distinctly non-modern one in the sense that he did not conceptualise it as irreversible state.

While some have sought to interpret, if in a qualified fashion, Morel’s reference to démence précoce as amounting to the “discovery” of schizophrenia, others have argued convincingly that Morel’s descriptive use of the term should not be considered in any sense as a precursor to the German psychiatrist Emil Kraepelin’s dementia praecox disease concept. This is due to the fact that their concepts of dementia differed significantly from each other, with Kraepelin employing the more modern sense of the word, and also that Morel was not describing a diagnostic category. Indeed, until the advent of Arnold Pick and Kraepelin, Morel’s term had vanished without a trace and there is little evidence to suggest that either Pick or indeed Kraepelin were even aware of Morel’s use of the term until long after they had published their own disease concepts bearing the same name. As Eugène Minkowski succinctly stated, ‘An abyss separates Morel’s démence précoce from that of Kraepelin.’

Degeneration Theory

Morel is known for creating degeneration theory in the 1850s. He began to develop his theory while he was the director of the mental asylum at Saint-Yon in northern France. In 19th century France, there was an increase in crime, sickness, and mental disorders, which interested Morel. He was determined to identify the underlying causes of this increase. Morel’s Catholic and radical political background greatly shaped his process. Morel noticed that the patients in the mental asylum with intellectual disability also had physical abnormalities like goiters. He was able to expand this idea when he noticed most people in the asylum had unusual physical characteristics. Morel’s degeneration theory was based on the idea that psychological disorders and other behavioural abnormalities were caused by an abnormal constitution. This also meant that he believed that there was a perfect type of human that degenerations altered. He believed that these abnormalities could be inherited and that there was a progressive worsening of the degeneration by generation. These traits were not specified pathologies, but rather an overall abnormality like a highly susceptible nervous system to disturbances from excessive toxins. The first generation started with neurosis, then, in the next generation, mental alienation. After the second generation, the mental alienation led to imbecility. Finally, the fourth generation was destined to be sterile.

In Morel’s theory, degeneration was synonymous with anything that was different from the natural or normal state. These abnormalities were caused by environmental influences like diet, disease, and moral depravities or traits that were passed from generation to generation like alcoholism and living in the slums. Due to the law of progressivity, these degenerations would get worse in each generation to produce more criminals and neurotics with worse degenerations. Over time, the degenerations would progress until later generations (specifically the fourth generation) were so idiotic that they were essentially sterile and the abnormal family would die out. This theory explained why there was an increase in mental disorders and also allowed Morel to relate very different diseases as caused by previous generations because they had become more variable over time. Since there was an increase in mental disorders, Morel believed that society was approaching extinction of the imbeciles. He believed that the most degenerative illness was insanity. Morel was able to categorise degenerations into four main categories:

  1. Hysteria;
  2. Moral insanity;
  3. Imbeciles; and
  4. Idiots.

In 1857, Morel published his degeneration theory in Traité des dégénérescences physiques, intellectuelles et morales de l’espèce humaine et des causes qui produisent ces variétés maladives. In his work, he included images of twelve patients that demonstrated the physical, mental, and moral traits that were evidence of degeneration. Some of these characteristics included altered ear shape, asymmetrical faces, extra digits, and high-domed palates that had psychological representations as well. Morel’s work was well received. It connected psychiatric medicine to general medicine to provide a complete and well-researched cause for a large social problem. It became dominant because it grounded moral treatment, which was questionable in this time period, in science. Morel’s theory also allowed psychiatrists who were unable to help their patients explain why they had not been successful. Degeneration theory meant that there were some psychological disorders that were genetic and could not be cured by a psychiatrist. It also explained all psychological disorders. If a psychiatrist could not find a physical cause of the disease, they could blame it on the individual’s constitution. It quickly spread throughout Europe with key figures spreading the information and using it to explain criminal psychology, personality disorders, and nervous disorders. Wilhem Griesinger introduced Morel’s theory to Germany, Valentin Magnan helped his ideas spread in France, and Cesare Lambroso brought Morel’s theory to Italy. In the 1880s, Morel’s degeneration theory was very important in French psychiatry and the majority of diagnostic certificates in French mental hospitals involved the words mental degeneracy.

Legacy

Morel is regarded as the father of dementia praecox and the degeneration theory. Both of these ideas helped understand mental illness as it was on the rise in 19th and 20th century France. Morel’s degeneration theory gained quick popularity across Europe, which allowed it to shape further scientific developments. It was used as the basis of body typology and disposition theories as well as Lombroso’s theory of anthropological criminology. His theory was highly ideological and provided a scientific rationale for the eugenics programmes used by the Nazis. He is also known for generating research programs to understand the effects of paternal drinking on children. Morel’s degeneration theory is a key influence on Émile Zola’s Les Rougon-Macquart about the environmental influences of violence, prostitution, and other immoral activities on two branches of a family during the Industrial Revolution. In Britain, the degeneration theory bolstered the eugenics and Social Darwinism movement. Karl Pearson and Sidney Webb justified selective breeding and immigration in Britain by trying to prevent the degeneration of the British race. Not all theorists accepted Morel’s work. Sigmund Freud, Karl Jaspers, Adolf Meyer, and Oswald Bumke rejected his ideas. Overall, while Morel’s degeneration theory is considered outdated by modern psychiatrists, Morel is credited with creating the modern biological approach to understanding psychiatric disorders.

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Who was Gregory Zilborg (1890-1959)?

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Introduction

Gregory Zilboorg (Russian: Григорий Зильбург, Ukrainian: Григорій Зільбург) (25 December 1890 to 17 September 1959) was a psychoanalyst and historian of psychiatry who is remembered for situating psychiatry within a broad sociological and humanistic context in his many writings and lectures.

Life and Career

Zilboorg was born into a Jewish family in Kiev, Ukraine on 25 December 1890 and studied medicine in St. Petersburg, where he worked under Vladimir Bekhterev. In 1917, after the February Revolution, he served as secretary to the Ministry of Labor under two prime ministers (Aleksandr Kerenskii and Georgii L’vov). When the Bolsheviks came to power, he fled to Kiev and established a reputation as a political journalist and drama critic.

Zilboorg emigrated to the United States in 1919 and supported himself by lecturing on the Chautauqua circuit and translating literature from Russian to English. Among the works he translated is Evgenii Zamiatin’s novel We, and Leonid Andreyev’s 1915 play He Who Gets Slapped Well received, that translation has been republished 17 times since that initial publication. In 1922 he began studying for his second medical degree, at Columbia University.

After graduating in 1926, he worked at the Bloomingdale Hospital and in 1931 began his psychoanalytic practice in New York City, having first been analysed in Berlin by Franz Alexander. From the 1930s onward, Zilboorg produced several volumes of lasting importance on the history of psychiatry. The Medical Man and the Witch During the Renaissance began as the Noguchi lectures at Johns Hopkins University in 1935. This volume was followed by A History of Medical Psychology in 1941 and Sigmund Freud in 1951. He also produced a series of clinical articles on subjects from the schizoid personality to postpartum depression – he considered the latter as rooted in ambivalence over motherhood and latent sadism[4] – and explored the effects of unresolved conflicts and countertransference effects of the analyst in the analytic situation.

Zilboorg’s patients included George Gershwin, Lillian Hellman, Ralph Ingersoll, Edward M.M. Warburg, Marshall Field, Kay Swift and James Warburg. The musical Lady in the Dark is reportedly based on Moss Hart’s experience of analysis with Zilboorg, who also examined other noted writers including Thomas Merton. Zilboorg married Ray Liebow in 1919 and they had two children (Nancy and Gregory, Jr.). He married Margaret Stone in 1946 and they had three children (Caroline, John and Matthew). His niece was cellist Olga Zilboorg.

Citing Susan Quinn,  author Ron Chernow  reports that Zilboorg engaged in unethical behavior including financial exploitation of patients. In an interview with Chernow, Edward M. M. Warburg reported that Zilboorg asked him for cash gifts and, in one instance, a mink coat for his wife.  A biography written by his daughter, The Life of Gregory Zilboorg (see further reading below) recounts in detail Zilboorg’s spiritual journey, his friendship with the Dominican Noël Mailloux, and his eventual conversion to Roman Catholicism.

Literary Archives

Zilboorg’s papers at the Beinecke Rare Book and Manuscript Library, Yale University, contain manuscripts of several of his publications as well as his personal correspondence with Margaret Stone Zilboorg.

Bibliography

Writings

  • The passing of the old order in Europe (1920)
  • The medical man and the witch during the renaissance (1935)
  • A history of medical psychology (1941)
  • Mind, Medicine, & Man (1943)
  • Sigmund Freud (1951)
  • Psychology of the criminal act and punishment (1954)
  • Psychoanalysis and Religion (1962)

Translations

  • He Who Gets Slapped by Leonid Andreyev, translated from the Russian with an introduction (1921)
  • We by Yevgeny Zamyatin, translated from the Russian (1924)
  • The criminal, the judge and the public; a psychological analysis by Franz Alexander and Hugo Staub, translated from the German (1931)
  • Outline of clinical psychoanalysis by Otto Fenichel, translated by Bertram D. Lewin and Gregory Zilboorg (1934)

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/Gregory_Zilboorg >; it is used under the Creative Commons Attribution-ShareAlike 3.0 Unported License (CC-BY-SA). You may redistribute it, verbatim or modified, providing that you comply with the terms of the CC-BY-SA.

Who was Bertram D. Lewin (1896-1971)?

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Introduction

Bertram David Lewin (30 November 1896 to 08 January 1971) was an American psychoanalyst who was both an acute clinician and a contributor to theory, particularly to the study of elation, and of the dream screen.

Training and Contributions

Lewin had a training analysis with Franz Alexander in Berlin in the 1920s, before publishing his first analytic article in 1930. This was followed by ten more over the next decade, on subjects ranging from diabetes and claustrophobia to the body as phallus. The main focus of his interest, however, was in manic states, which he saw as characterised by fleeting identifications with a multiple of outside figures.

After the war, he published the fruits of his investigations in The Psychoanalysis of Elation (1951). There he stressed the role of denial in mania – denial particularly of feelings of separation and loss. He also explored the paradox in elation’s dark counterpart, depression, whereby the melancholic in seeking to punish the effigy of their loved one in fact punishes themselves having incorporated this effigy.

By that point he had also published his seminal article (1946) on the dream screen – the backcloth formed from primitive memories of the breast onto which the dream is projected. The concept would be fruitfully followed up both within analysis, and in the context of film theory.

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/Bertram_D._Lewin >; it is used under the Creative Commons Attribution-ShareAlike 3.0 Unported License (CC-BY-SA). You may redistribute it, verbatim or modified, providing that you comply with the terms of the CC-BY-SA.

Who is Carol Ryff?

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Introduction

Carol Diane Ryff is an American academic and psychologist. She received her doctorate in 1978.

Outline

She is known for studying psychological well-being and psychological resilience.

Ryff is the Hilldale Professor of psychology at the University of Wisconsin-Madison, where she directs the Institute on Ageing.

Ryff developed the six-factor model of psychological well-being.

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/Carol_Ryff >; it is used under the Creative Commons Attribution-ShareAlike 3.0 Unported License (CC-BY-SA). You may redistribute it, verbatim or modified, providing that you comply with the terms of the CC-BY-SA.

What is the Twelve-Step Programme?

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Introduction

Twelve-step programmes are international mutual aid programs supporting recovery from substance addictions, behavioural addictions and compulsions. Developed in the 1930s, the first twelve-step programme, Alcoholics Anonymous (AA), founded by Bill Wilson and Bob Smith, aided its membership to overcome alcoholism. Since that time dozens of other organisations have been derived from AA’s approach to address problems as varied as drug addiction, compulsive gambling, sex, and overeating. All twelve-step programmes utilise a version of AA’s suggested twelve steps first published in the 1939 book Alcoholics Anonymous: The Story of How More Than One Hundred Men Have Recovered from Alcoholism.

As summarised by the American Psychological Association (APA), the process involves the following:

  • Admitting that one cannot control one’s alcoholism, addiction, or compulsion;
  • Coming to believe in a Higher Power that can give strength;
  • Examining past errors with the help of a sponsor (experienced member);
  • Making amends for these errors;
  • Learning to live a new life with a new code of behaviour; and
  • Helping others who suffer from the same alcoholism, addictions, or compulsions.

Overview

Twelve-step methods have been adapted to address a wide range of alcoholism, substance abuse, and dependency problems. Over 200 mutual aid organisations – often known as fellowships—with a worldwide membership of millions have adopted and adapted AA’s 12 Steps and 12 Traditions for recovery. Narcotics Anonymous was formed by addicts who did not relate to the specifics of alcohol dependency.

Demographic preferences related to the addicts’ drug of choice has led to the creation of Cocaine Anonymous, Crystal Meth Anonymous and Marijuana Anonymous. Behavioural issues such as compulsion for or addiction to gambling, crime, food, sex, hoarding, getting into debt and work are addressed in fellowships such as Gamblers Anonymous, Overeaters Anonymous, Sexaholics Anonymous and Debtors Anonymous.

Auxiliary groups such as Al-Anon and Nar-Anon, for friends and family members of alcoholics and addicts, respectively, are part of a response to treating addiction as a disease that is enabled by family systems. Adult Children of Alcoholics (ACA or ACOA) addresses the effects of growing up in an alcoholic or otherwise dysfunctional family. Co-Dependents Anonymous (CoDA) addresses compulsions related to relationships, referred to as co-dependency.

Brief History

Alcoholics Anonymous (AA), the first twelve-step fellowship, was founded in 1935 by Bill Wilson and Dr. Robert Holbrook Smith, known to AA members as “Bill W.” and “Dr. Bob”, in Akron, Ohio. In 1946 they formally established the twelve traditions to help deal with the issues of how various groups could relate and function as membership grew. The practice of remaining anonymous (using only one’s first names) when interacting with the general public was published in the first edition of the AA Big Book.

As AA chapters were increasing in number during the 1930s and 1940s, the guiding principles were gradually defined as the Twelve Traditions. A singleness of purpose emerged as Tradition Five: “Each group has but one primary purpose—to carry its message to the alcoholic who still suffers”. Consequently, drug addicts who do not suffer from the specifics of alcoholism involved in AA hoping for recovery technically are not welcome in “closed” meetings unless they have a desire to stop drinking alcohol.

The principles of AA have been used to form numerous other fellowships specifically designed for those recovering from various pathologies; each emphasizes recovery from the specific malady which brought the sufferer into the fellowship.

The Twelve Steps

The following are the original twelve steps as published by Alcoholics Anonymous:[11]

  1. We admitted we were powerless over alcohol—that our lives had become unmanageable.
  2. Came to believe that a power greater than ourselves could restore us to sanity.
  3. Made a decision to turn our will and our lives over to the care of God as we understood Him.
  4. Made a searching and fearless moral inventory of ourselves.
  5. Admitted to God, to ourselves, and to another human being the exact nature of our wrongs.
  6. Were entirely ready to have God remove all these defects of character.
  7. Humbly asked Him to remove our shortcomings.
  8. Made a list of all persons we had harmed, and became willing to make amends to them all.
  9. Made direct amends to such people wherever possible, except when to do so would injure them or others.
  10. Continued to take personal inventory, and when we were wrong, promptly admitted it.
  11. Sought through prayer and meditation to improve our conscious contact with God as we understood Him, praying only for knowledge of His will for us and the power to carry that out.
  12. Having had a spiritual awakening as the result of these steps, we tried to carry this message to alcoholics and to practice these principles in all our affairs.

Where other twelve-step groups have adapted the AA steps as guiding principles, step one is generally updated to reflect the focus of recovery. For example, in Overeaters Anonymous, the first step reads, “We admitted we were powerless over compulsive overeating—that our lives had become unmanageable.” The third step is also sometimes altered to remove gender-specific pronouns.

The Twelve Traditions

The Twelve Traditions accompany the Twelve Steps. The Traditions provide guidelines for group governance. They were developed in AA in order to help resolve conflicts in the areas of publicity, politics, religion, and finances. Alcoholics Anonymous’ Twelve Traditions are:

  1. Our common welfare should come first; personal recovery depends upon AA unity.
  2. For our group purpose there is but one ultimate authority—a loving God as He may express Himself in our group conscience. Our leaders are but trusted servants; they do not govern.
  3. The only requirement for AA membership is a desire to stop drinking.
  4. Each group should be autonomous except in matters affecting other groups or AA as a whole.
  5. Each group has but one primary purpose—to carry its message to the alcoholic who still suffers.
  6. An AA group ought never endorse, finance, or lend the AA name to any related facility or outside enterprise, lest problems of money, property, and prestige divert us from our primary purpose.
  7. Every AA group ought to be fully self-supporting, declining outside contributions.
  8. Alcoholics Anonymous should remain forever non-professional, but our service centers may employ special workers.
  9. AA, as such, ought never be organised; but we may create service boards or committees directly responsible to those they serve.
  10. Alcoholics Anonymous has no opinion on outside issues; hence the AA name ought never be drawn into public controversy.
  11. Our public relations policy is based on attraction rather than promotion; we need always to maintain personal anonymity at the level of press, radio, and films.
  12. Anonymity is the spiritual foundation of all our traditions, ever reminding us to place principles before personalities.

The Process

In the twelve-step programme, the human structure is symbolically represented in three dimensions: physical, mental, and spiritual. The problems the groups deal with are understood to manifest themselves in each dimension. For addicts and alcoholics, the physical dimension is best described by the allergy-like bodily reaction resulting in the compulsion to continue using substances even when it’s harmful or wanting to quit. The statement in the First Step that the individual is “powerless” over the substance-abuse related behaviour at issue refers to the lack of control over this compulsion, which persists despite any negative consequences that may be endured as a result.

The mental obsession is described as the cognitive processes that cause the individual to repeat the compulsive behaviour after some period of abstinence, either knowing that the result will be an inability to stop or operating under the delusion that the result will be different. The description in the First Step of the life of the alcoholic or addict as “unmanageable” refers to the lack of choice that the mind of the addict or alcoholic affords concerning whether to drink or use again. The illness of the spiritual dimension, or “spiritual malady,” is considered in all twelve-step groups to be self-centeredness. The process of working the steps is intended to replace self-centeredness with a growing moral consciousness and a willingness for self-sacrifice and unselfish constructive action. In twelve-step groups, this is known as a “spiritual awakening.” This should not be confused with abreaction, which produces dramatic, but temporary, changes. As a rule, in twelve-step fellowships, spiritual awakening occurs slowly over a period of time, although there are exceptions where members experience a sudden spiritual awakening.

In accordance with the First Step, twelve-step groups emphasize self-admission by members of the problem they are recovering from. It is in this spirit that members often identify themselves along with an admission of their problem, often as “Hi, I’m [first name only], and I’m an alcoholic”.

Sponsorship

A sponsor is a more experienced person in recovery who guides the less-experienced aspirant (“sponsee”) through the program’s twelve steps. New members in twelve-step programmes are encouraged to secure a relationship with at least one sponsor who both has a sponsor and has taken the twelve steps themselves. Publications from twelve-step fellowships emphasize that sponsorship is a “one on one” non-hierarchical relationship of shared experiences focused on working the Twelve Steps. According to Narcotics Anonymous:

Sponsors share their experience, strength, and hope with their sponsees… A sponsor’s role is not that of a legal adviser, a banker, a parent, a marriage counsellor, or a social worker. Nor is a sponsor a therapist offering some sort of professional advice. A sponsor is simply another addict in recovery who is willing to share his or her journey through the Twelve Steps.

Sponsors and sponsees participate in activities that lead to spiritual growth. Experiences in the programme are often shared by outgoing members with incoming members. This rotation of experience is often considered to have a great spiritual reward. These may include practices such as literature discussion and study, meditation, and writing. Completing the programme usually implies competency to guide newcomers which is often encouraged. Sponsees typically do their Fifth Step, review their moral inventory written as part of the Fourth Step, with their sponsor. The Fifth Step, as well as the Ninth Step, have been compared to confession and penitence. Michel Foucault, a French philosopher, noted such practices produce intrinsic modifications in the person—exonerating, redeeming and purifying them; relieves them of their burden of wrong, liberating them and promising salvation.

The personal nature of the behavioural issues that lead to seeking help in twelve-step fellowships results in a strong relationship between sponsee and sponsor. As the relationship is based on spiritual principles, it is unique and not generally characterised as “friendship”. Fundamentally, the sponsor has the single purpose of helping the sponsee recover from the behavioural problem that brought the sufferer into twelve-step work, which reflexively helps the sponsor recover.

A study of sponsorship as practiced in Alcoholics Anonymous and Narcotics Anonymous found that providing direction and support to other alcoholics and addicts is associated with sustained abstinence for the sponsor, but suggested that there were few short-term benefits for the sponsee’s one-year sustained abstinence rate.

Effectiveness

Alcoholics Anonymous is the largest of all of the twelve-step programmes (from which all other twelve-step programmes are derived), followed by Narcotics Anonymous; the majority of twelve-step members are recovering from addiction to alcohol or other drugs. The majority of twelve-step programmes, however, address illnesses other than substance addiction. For example, the third-largest twelve-step programme, Al-Anon, assists family members and friends of people who have alcoholism and other addictions. About twenty percent of twelve-step programmes are for substance addiction recovery, the other eighty percent address a variety of problems from debt to depression. It would be an error to assume the effectiveness of twelve-step methods at treating problems in one domain translates to all or to another domain.

A 2020 Cochrane review of Alcoholics Anonymous showed that participation in AA resulted in more alcoholics being abstinent from alcohol and for longer periods of time than cognitive behavioural therapy and motivational enhancement therapy, and as effective as these in other measures. The 2020 review did not compare twelve step programmes to the use of disulfiram or naltrexone, though some patients did receive these medications. These medications are considered the standard of care in alcohol use disorder treatment among medical experts and have demonstrated efficacy in randomised controlled trials in promoting alcohol abstinence. A systematic review published in 2017 found that twelve-step programmes for reducing illicit drug use are neither better nor worse than other interventions.

Criticism

In the past, some medical professionals have criticised 12-step programmes as “a cult that relies on God as the mechanism of action” and as lacking any experimental evidence in favour of its efficacy. Ethical and operational issues had prevented robust randomised controlled trials from being conducted comparing 12-step programmes directly to other approaches. More recent studies employing non-randomised and quasi-experimental studies have shown 12-step programmes provide similar benefit compared to motivational enhancement therapy (MET) and cognitive behavioural therapy (CBT), and were more effective in producing continuous abstinence and remission compared to these approaches.

Confidentiality

The Twelve Traditions encourage members to practice the spiritual principle of anonymity in the public media and members are also asked to respect each other’s confidentiality. This is a group norm, however, and not legally mandated; there are no legal consequences to discourage those attending twelve-step groups from revealing information disclosed during meetings. Statutes on group therapy do not encompass those associations that lack a professional therapist or clergyman to whom confidentiality and privilege might apply. Professionals and paraprofessionals who refer patients to these groups, to avoid both civil liability and licensure problems, have been advised that they should alert their patients that, at any time, their statements made in meetings may be disclosed.

Cultural Identity

One review warned of detrimental iatrogenic effects of twelve-step philosophy and labelled the organisations as cults, while another review asserts that these programs bore little semblance to religious cults and that the techniques used appeared beneficial to some. Another study found that a twelve-step program’s focus on self-admission of having a problem increases deviant stigma and strips members of their previous cultural identity, replacing it with the deviant identity. Another study asserts that the prior cultural identity may not be replaced entirely, but rather members found adapted a bicultural identity.

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/Twelve-step_program >; it is used under the Creative Commons Attribution-ShareAlike 3.0 Unported License (CC-BY-SA). You may redistribute it, verbatim or modified, providing that you comply with the terms of the CC-BY-SA.

An Overview of Posttraumatic Growth

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Introduction

In psychology, posttraumatic growth (PTG) is positive psychological change experienced as a result of struggling with highly challenging, highly stressful life circumstances.

These circumstances represent significant challenges to the adaptive resources of the individual, and pose significant challenges to the individual’s way of understanding the world and their place in it. Posttraumatic growth involves “life-changing” psychological shifts in thinking and relating to the world and the self, that contribute to a personal process of change, that is deeply meaningful.

Brief History

The general understanding that suffering and distress can potentially yield positive change is thousands of years old. For example, some of the early ideas and writing of the ancient Hebrews, Greeks, and early Christians, as well as some of the teachings of Hinduism, Buddhism, Islam and the Baháʼí Faith contain elements of the potentially transformative power of suffering. Attempts to understand and discover the meaning of human suffering represent a central theme of much philosophical inquiry and appear in the works of novelists, dramatists and poets.

Traditional psychology’s equivalent to thriving is resilience, which is reaching the previous level of functioning before a trauma, stressor, or challenge. The difference between resilience and thriving is the recovery point – thriving goes above and beyond resilience, and involves finding benefits within challenges.

The term “posttraumatic growth” was coined by psychologists at the University of North Carolina at Charlotte. According to Tedeschi, as many as 89% of survivors report at least one aspect of posttraumatic growth, such as a renewed appreciation for life.

Variants of the idea have included Crystal Park’s proposed stress related growth model, which highlighted the derived sense of meaning in the context of adjusting to challenging and stressful situations, and Joseph and Linley’s proposed adversarial growth model, which linked growth with psychological wellbeing. According to the adversarial growth model, whenever an individual is experiencing a challenging situation, they can either integrate the traumatic experience into their current belief system and worldviews or they can modify their beliefs based on their current experiences. If the individual positively accommodates the trauma-related information and assimilates prior beliefs, psychological growth can occur following adversity.

Causes

Posttraumatic growth occurs with the attempts to adapt to highly negative sets of circumstances that can engender high levels of psychological distress such as major life crises, which typically engender unpleasant psychological reactions.[1] Growth does not occur as a direct result of trauma; rather, it is the individual’s struggle with the new reality in the aftermath of trauma that is crucial in determining the extent to which posttraumatic growth occurs. Encouragingly, reports of growth experiences in the aftermath of traumatic events far outnumber reports of psychiatric disorders, since continuing personal distress and growth often coexist.

As far as predictors of posttraumatic growth, a number of factors have been associated with adaptive growth following exposure to a trauma. Spirituality has been shown to highly correlate with posttraumatic growth and in fact, many of the most deeply spiritual beliefs are a result of trauma exposure. Social support has been well documented as a buffer to mental illness and stress response. In regards to posttraumatic growth, not only are high levels of pre-exposure social support associated with growth, but there is some neurobiological evidence to support the idea that support will modulate a pathological response to stress in the hypothalamic-pituitary-adrenocortical (HPA) pathway in the brain. As Richard G. Tedeschi and other posttraumatic growth researchers have found, the ability to accept situations that cannot be changed is crucial for adapting to traumatic life events. They call it “acceptance coping”, and have determined that coming to terms with reality is a significant predictor of posttraumatic growth. It is also alleged, though currently under further investigation, that opportunity for emotional disclosure can lead to posttraumatic growth though did not significantly reduce post-traumatic stress symptomology. Gender roles did not reliably predict posttraumatic growth though are indicative of the type of trauma that an individual experiences. Women tend to experience victimisation on a more individual and interpersonal level (e.g. sexual victimisation) while men tend to experience more systemic and collective traumas (e.g. military and combat). Given that group dynamics appear to play a predictive role in posttraumatic growth, it can be argued that the type of exposure may indirectly predict growth in men.

Posttraumatic Growth and Personality

Historically, personality traits have been depicted as being stable following the age of 30. Since 1994, research findings suggested that personality traits can change in response to life transition events during middle and late adulthood. Life transition events may be related to work, relationships, or health. Moderate amounts of stress were associated with improvements in the traits of mastery and toughness. Individuals experiencing moderate amounts of stress were found to be more confident about their abilities and had a better sense of control over their lives. Further, moderate amounts of stress were also associated with better resilience, which can be defined as successful recovery to baseline following stress. An individual who experienced moderate amounts of stressful events was more likely to develop coping skills, seek support from their environment, and experience more confidence in their ability to overcome adversity.

Posttraumatic Growth

Posttraumatic growth refers to positive psychological change resulting from a struggle with traumatic or highly challenging life circumstances. Experiencing a traumatic event can have a transformational role in personality among certain individuals and facilitate growth. For example, individuals who have experienced trauma have been shown to exhibit greater optimism, positive affect, and satisfaction with social support, as well as increases in the number of social supportive resources. Similarly, research reveals personality changes among spouses of terminal cancer patients suggesting such traumatic life transitions facilitated increases in interpersonal orientation, prosocial behaviours, and dependability scores.

Importantly, experiencing a traumatic life event per se does not lead to posttraumatic growth. Not everyone who experiences a traumatic event will directly develop posttraumatic growth. Rather, an individual’s emotional response to the traumatic event is significant in determining the long-term outcome of that trauma. The outcome of traumatic events can be negatively impacted by factors occurring during and after the trauma, potentially increasing the risk of developing posttraumatic stress disorder, or other mental health difficulties.

Further, characteristics of the trauma and personality dynamics of the individual experiencing the trauma each independently contributed to posttraumatic growth. If the amounts of stress are too low or too overwhelming, a person cannot cope with the situation. Personality dynamics can either facilitate or impede posttraumatic growth, regardless of the impact of traumatic events.

Mixed Findings

Research of posttraumatic growth is emerging in the field of personality psychology, with mixed findings. Several researchers examined posttraumatic growth and its associations with the big five personality model. Posttraumatic growth was found to be associated with greater agreeableness, openness, and extraversion. Agreeableness relates to interpersonal behaviours which include trust, altruism, compliance, honesty, and modesty. Individuals who are agreeable are more likely to seek support when needed and to receive it from others. Higher scores on the agreeableness trait can facilitate the development of posttraumatic growth.

Individuals who score high on openness scales are more likely to be curious, open to new experiences, and emotionally responsive to their surroundings. It is hypothesized that following a traumatic event, individuals who score high on openness would more readily reconsider their beliefs and values that may have been altered. Openness to experiences is thus key for facilitating posttraumatic growth. Individuals who score high on extraversion were more likely to adopt more problem-solving strategies, cognitive restructuring, and seek more support from others. Individuals who score high on extraversion use coping strategies that enable posttraumatic growth. Research among veterans and among children of prisoners of war suggested that openness and extraversion contributed to posttraumatic growth.

Research among community samples suggested that openness, agreeableness, and conscientiousness contributed to posttraumatic growth. Individuals who score high on conscientiousness tend to be better at self-regulating their internal experience, have better impulse control, and are more likely to seek achievements across various domains. The conscientiousness trait has been associated with better problem-solving and cognitive restructuring. As such, individuals who are conscientious are more likely to better adjust to stressors and exhibit posttraumatic growth.

Other research among bereaved caregivers and among undergraduates indicated that posttraumatic growth was associated with extraversion, agreeableness, and conscientiousness. As such, the findings linking the big five personality traits with posttraumatic growth are mixed.

Trauma Types, Personality Dynamics, and Posttraumatic Growth

Recent research is examining the influence of trauma types and personality dynamics on posttraumatic growth. Individuals who aspire to standards and orderliness are more likely to develop posttraumatic growth and better overall mental health. It is hypothesized that such individuals can better process the meaning of hardships as they experience moderate amounts of stress. This tendency can facilitate positive personal growth. On the other hand, it was found that individuals who have trouble in regulating themselves are less likely to develop posttraumatic growth and more likely to develop trauma-spectrum disorders and mood disorders. This is in line with past research that suggested that individuals who scored higher on self-discrepancy were more likely to score higher on neuroticism and exhibit poor coping. Neuroticism relates to an individual’s tendency to respond with negative emotions to threat, frustration, or loss. As such, individuals with high neuroticism and self-discrepancy are less likely to develop posttraumatic growth. Research has highlighted the important role that collective processing of emotional experiences has on posttraumatic growth. Those who are more capable of engaging with their emotional experiences due to crisis and trauma, and make meaning of these are more likely to increase in their resilience and community engagement following the disaster. Furthermore, collective processing of these emotional experiences leads to greater individual growth and collective solidarity and belongingness.

Characteristics

People who have experienced posttraumatic growth report changes in the following 5 factors: Appreciation of life; Relating to others; Personal strength; New possibilities; and Spiritual, existential or philosophical change. Two personality characteristics that may affect the likelihood that people can make positive use of the aftermath of traumatic events that befall them include extraversion and openness to experience. Also, optimists may be better able to focus attention and resources on the most important matters, and disengage from uncontrollable or unsolvable problems. The ability to grieve and gradually accept trauma could also increase the likelihood of growth. It also benefits a person to have supportive others that can aid in posttraumatic growth by providing a way to craft narratives about the changes that have occurred, and by offering perspectives that can be integrated into schema change. These relationships help develop narratives; these narratives of trauma and survival are always important in posttraumatic growth because the development of these narratives forces survivors to confront questions of meaning and how answers to those questions can be reconstructed. Individual differences in coping strategies set some people on a maladaptive spiral, whereas others proceed on an adaptive spiral. With this in mind, some early success in coping could be a precursor to posttraumatic growth. A person’s level of confidence could also play a role in her or his ability to persist into growth or, out of lack of confidence, give up.

In 2011 Iversen and Christiansen & Elklit suggested that predictors of growth have different effects on PTG on micro-, meso-, and macro level, and a positive predictor of growth on one level can be a negative predictor of growth on another level. This might explain some of the inconsistent research results within the area.

Posttraumatic growth has been studied in children to a lesser extent. A review by Meyerson and colleagues found various relations between social and psychological factors and posttraumatic growth in children and adolescents, but concluded that fundamental questions about its value and function remain.

Theories and Findings

Resilience

In general, research in psychology shows that people are resilient overall. For example, Southwick and Charney, in a study of 250 prisoners of war from the Vietnam War, showed that participants developed much lower rates of depression and PTSD symptoms than expected. Donald Meichenbaum estimated that 60% of North Americans will experience trauma in their lifetime, and of these while no one is unscathed, some 70% show resilience and 30% show harmful effects. Similarly, 68 million women of the 150 million in America will be victimised over their lifetime, but a shocking 10% will suffer insofar as they must seek help from mental health professionals.

In general, traditional psychology’s approach to resiliency as exhibited in the studies above is a problem-oriented one, assuming that PTSD is the problem and that resiliency just means to avoid or fix that problem in order to maintain baseline well-being. This type of approach fails to acknowledge any growth that might occur beyond the previously set baseline, however. Positive psychology’s idea of thriving attempts to reconcile that failure. A meta-analysis of studies conducted by Shakespeare-Finch and Lurie-Beck in this area indicates that there is actually an association between PTSD symptoms and posttraumatic growth. The null hypothesis that there is no relationship between the two was rejected for the study. The correlation between the two was significant and was found to be dependent upon the nature of the event and the person’s age. For example, survivors of sexual assault show less posttraumatic growth than survivors of natural disaster. Ultimately, however, the meta-analysis serves to show that PTSD and posttraumatic growth are not mutually exclusive ends of a recovery spectrum and that they may actually co-occur during a successful process to thriving.

It is important to note that while aspects of resilience and growth aid an individual’s psychological well-being, they are not the same thing. Dr. Richard Tedeschi and Dr. Erika Felix specifically note that resilience suggests bouncing back and returning to one’s previous state of being, whereas post-traumatic growth fosters a transformed way of being or understanding for an individual. Often, traumatic or challenging experiences force an individual to re-evaluate core beliefs, values, or behaviours on both cognitive and emotional levels; the idea of post-traumatic growth is therefore rooted in the notion that these beliefs, values, or behaviours come with a new perspective and expectation after the event. Thus, post-traumatic growth centres around the concept of change, whereas resilience suggests the return to previous beliefs, values, or lifestyles.

Thriving

To understand the significance of thriving in the human experience, it is important to understand its role within the context of trauma and its separation from traditional psychology’s idea of resilience. Implicit in the idea of thriving and resilience both is the presence of adversity. O’Leary and Ickovics created a four-part diagram of the spectrum of human response to adversity, the possibilities of which include:

  1. Succumbing to adversity;
  2. Surviving with diminished quality of life;
  3. Resiliency (returning to baseline quality of life); and
  4. Thriving.

Thriving includes not only resiliency, but an additional further improvement over the quality of life previous to the adverse event.

Thriving in positive psychology definitely aims to promote growth beyond survival, but it is important to note that some of the theories surrounding the causes and effects of it are more ambiguous. Literature by Carver indicates that the concept of thriving is a difficult one to define objectively. He makes the distinction between physical and psychological thriving, implying that while physical thriving has obvious measurable results, psychological thriving does not as much. This is the origin of much ambiguity surrounding the concept. Carver lists several self-reportable indicators of thriving: greater acceptance of self, change in philosophy, and a change in priorities. These are factors that generally lead a person to feel that they have grown, but obviously are difficult to measure quantitatively.

The dynamic systems approach to thriving attempts to resolve some of the ambiguity in the quantitative definition of thriving, citing thriving as an improvement in adaptability to future trauma based on their model of attractors and attractor basins. This approach suggests that reorganisation of behaviours is required to make positive adaptive behaviour a more significant attractor basin, which is an area the system shows a tendency toward.

In general, as pointed out by Carver, the idea of thriving seems to be one that is hard to remove from subjective experience. However, work done by Meichenbaum to create his Posttraumatic Growth Inventory helps to set forth a more measurable map of thriving. The five fields of posttraumatic growth that Meichenbaum outlined include: relating to others, new possibilities, personal strength, spiritual change, and appreciation for life. Though literature that addresses “thriving” specifically is sparse, there is much research in the five areas Meichenbaum cites as facilitating thriving, all of which supports the idea that growth after adversity is a viable and significant possibility for human well-being.

Aspects of Posttraumatic Growth

Another attempt at quantitatively charting the concept of thriving is via the Posttraumatic Growth Inventory. The inventory has 21 items and is designed to measure the extent to which one experiences personal growth after adversity. The inventory includes elements from five key areas: relating to others, new possibilities, personal strength, spiritual change, and appreciation for life. These five categories are reminiscent of the subjective experiences Carver struggled to quantify in his own literature on thriving, but are imposed onto scales to maintain measurability. When considering the idea of thriving from the five-point approach, it is easier to place more research from psychology within the context of thriving. Additionally, a short form version of the Posttraumatic Growth Inventory has been created with only 10 items, selecting two questions for each of the five subscales. Studies have been conducted to better understand the validity of this scale and some have found that self-reported measures of posttraumatic growth are unreliable. Frazier et al. (2009) reported that further improvement could be made to this inventory to better capture actual change.

One of the key facets of posttraumatic growth set forth by Meichenbaum is relating to others. Accordingly, much work has been done to indicate that social support resources are extremely important to the facilitation of thriving. House, Cohen, and their colleagues indicate that perception of adequate social support is associated with improved adaptive tendency. This idea of better adaptive tendency is central to thriving in that it results in an improved approach to future adversity. Similarly, Hazan and Shaver reason that social support provides a solid base of security for human endeavour. The idea of human endeavour here is echoed in another of Meichenbaum’s facets of posttraumatic growth, new possibilities, the idea being that a person’s confidence to “endeavour” in the face of novelty is a sign of thriving.

Concurrent with a third facet of Meichenbaum’s posttraumatic growth, personal strength, a meta analysis of six qualitative studies done by Finfgeld focuses on courage as a path to thriving. Evidence from the analysis indicates that the ability to be courageous includes acceptance of reality, problem-solving, and determination. This not only directly supports the significance of personal strength in thriving, but can also be drawn to Meichenbaum’s concept of “new possibilities” through the idea that determination and adaptive problem-solving aid in constructively confronting new possibilities. Besides this, it was found in Finfgeld’s study that courage is promoted and sustained by intra- and interpersonal forces, further supporting Meichenbaum’s concept of “relating to others” and its effect on thriving.

On Meichenbaum’s idea of appreciation for life, research done by Tyson on a sample of people 2–5 years into grieving processing reveals the importance of creating meaning. The studies show that coping with bereavement optimally does not only involve just “getting over it and moving on”, but should also include creating meaning to facilitate the best recovery. The study showed that stories and creative forms of expression increase growth following bereavement. This evidence is supported strongly by work done by Michael and Cooper focused on facets of bereavement that facilitate growth including “the age of the bereaved”, “social support”, “time since death”, “religion”, and “active cognitive coping strategies”. The idea of coping strategies is echoed through the importance thriving places on improving adaptability. The significance of social support to growth found by Michael and Cooper clearly supports Meichenbaum’s concept of “relating to others”. Similarly, the significance of religion echoes Meichenbaum’s “spiritual change” facet of posttraumatic growth.

Positive Psychology

Posttraumatic growth can be seen as a form of positive psychology. In the 1990s, the field of psychology began a movement towards understanding positive psychological outcomes after trauma. Researchers initially referred to this phenomenon in number of different ways, “positive life changes”, “growing in the aftermath of suffering”, and “positive adaptation to trauma”. But it wasn’t until Tedeschi & Calhoun created the “Posttraumatic Growth Inventory (PTGI)” in 1996 in which the term “Posttraumatic Growth (PTG)” was born. Around the same time, a new area of strengths-based psychology emerged.

Positive Psychology

Positive psychology involves studying positive mental processes aimed at understanding positive psychological outcomes and “healthy” individuals. This framework was intended to serve as an answer to “mental illness” focused psychology. The core ideals of positive psychology are included, but not limited to:

  • Positive personality traits (optimism, subjective well-being, happiness, self-determination)
  • Authenticity
  • Finding meaning and purpose (self-actualisation)
  • Spirituality
  • Healthy interpersonal relationships
  • Satisfaction with life
  • Gratitude

Posttraumatic Growth

The concept of PTG has been described as a part of the positive psychology movement. Since PTG describes positive outcomes post trauma rather than negative outcomes, it falls under the category of positive psychological changes. Positive psychology intends to lay claim on all capacities of positive mental functioning. So, even though PTG (as a defined concept) was not initially described in the positive psychology framework, it is presently included in positive psychological theories. This is reinforced by the parallels between the core concepts of positive psychology and PTG. This is observable through comparing the 5 domains of the PTGI with the core ideals of positive psychology.

The Domains of the Posttraumatic Growth Inventory and Their Relationship to the Ideals of Positive Psychology

Positive psychological changes and outcomes are defined as a part of positive psychology. PTG is specifically the positive psychological changes post-trauma. The domains of PTG are defined as the different areas of positive psychological changes that are possible post-trauma. The PTGI, a measure designed by Tedeschi and Calhoun in 1996, measures PTG across the following areas or domains:

DomainOutline
New PossibilitiesThe positive psychological changes described by the domain of “New Possibilities” are developing new interests, establishing a new path in life, doing better things with one’s life, new opportunities, and an increased likelihood to change what is needed. This can be compared to the “finding meaning and purpose” core ideal of positive psychology.
Relating to OthersThe positive psychological changes described by the domain “Relating to Others” are increased reliability on others in times of trouble, greater sense of closeness with others, willingness to express emotions to others, increased compassion for others, increased effort in relationships, greater appreciation of how wonderful people are, and increased acceptance about needing others. This can be compared to the “healthy interpersonal relationships” core ideal of positive psychology.
Personal StrengthThe positive psychological changes described by the domain “Personal Strength” are a greater feeling of self-reliance, increased ability to handle difficulties, improved acceptance of life outcomes and new discovery of mental strength. This can be compared to the “positive personality traits (self-determination, optimism)” core ideals of positive psychology.
Spiritual ChangeThe positive psychological changes described by the domain “Spiritual Change” are a better understanding of spiritual matters and a stronger religious (or spiritual) faith. This can be compared to the “spirituality and authenticity” core ideal of positive psychology.
Appreciation of LifeThe positive psychological changes described by the domain “Appreciation of Life” are changed priorities regarding what is important in life, a greater appreciation of the value of one’s own life, and increased appreciation of each day. This can be compared to the “satisfaction with life” core ideal of positive psychology.

In 2004, Tedeschi & Calhoun released an updated framework of PTG. The overlaps between positive psychology and posttraumatic growth demonstrate an overwhelming association between these frameworks. However, Tedeschi and Calhoun note that even though these domains describe positive psychological changes post-trauma, the presence of PTG does not necessarily rule out the occurrence of any simultaneous negative post-trauma mental processes nor negative outcomes (such as psychological distress).

Clinical Application of Posttraumatic Growth within Positive Psychology

In a clinical setting, PTG is often included as a part of positive psychology in terms of methodology and treatment goals. Positive psychology interventions (PPI) generally include a multidimensional, therapeutic approach in which psychological tests are measurements to track progress. For clinical PPI involving recovery from trauma, there is usually at least one measure of PTG. Most trauma research and clinical intervention focuses on evaluating the negative outcomes post-trauma. But from a positive psychological perspective, a strengths-based approach might be more relevant for clinical intervention aimed at recovery. While PTG has been effectively measured in a number of relevant areas of psychology, it has been especially successful in health psychology.

In the exploration of PTG in health psychology settings (hospitals, long-term care clinics, etc.), well-being (a core ideal of positive psychology [60]) was linked to increased PTG in patients. PTG is seen more often in health psychology settings when PPI are utilised. While the focus in health psychology settings is to foster resilience, new research indicates that health psychology practitioners, doctors, and nurses should also aim to increase positive psychological outcomes (such as PTG) as a part of their recovery goals. Resilience is also central to positive psychology and is involved with PTG. Resilience has been distinguished as a pathway to PTG, but its exact relationship is currently still being explored. That being said, they are both positive psychological processes with strong ties to positive psychology.

Positive Psychology Treatment Results

The use of PPI post-trauma is not only effective in increasing PTG, but it has also been shown to reduce negative posttraumatic symptoms. These reductions on posttraumatic stress symptoms and increases in PTG have been demonstrated to be long-lasting. When participants were followed up at 12 months post PPI, not only was the PTG still present, it actually increased over time. PPI targeted at reducing stress have demonstrated promising results across a large number of studies.

Conclusion

Over the last 25 years, PTG has demonstrated its place in the framework of positive psychology in theory and in practice. The theoretical framework put forth by Seligman & Csikszentmihalyi and Tedeschi & Calhoun, have substantial overlap and both cite “positive psychological changes”. While positive psychology speaks to a general focus on positive aspects of human psychology, PTG speaks specifically to positive psychological change after trauma. This would inherently make PTG a sub-category of positive psychology. PTG has also been referred to in the literature as perceived benefits, positive changes, stress-related growth, and adversarial growth. However, it is made clear that regardless of the terminology, it is based is positive mental changes, which is the essence of positive psychology.

Positive Disintegration

The theory of positive disintegration by Kazimierz Dąbrowski is a theory that postulates that symptoms such as psychological tension and anxiety could be signs that a person might be in positive disintegration. The theory proposes that this can happen when an individual rejects previously adopted values (relating to their physical survival and their place in society), and adopts new values that are based on the higher possible version of who they can be. Rather than seeing disintegration as a negative state, the theory proposes that is a transient state which allows an individual to grow towards their personality ideal. The theory stipulates that individuals who have a high development potential (i.e. those with overexcitabilities), have a higher chance of re-integrating at a higher level of development, after disintegration. Scholarly work is needed to ascertain whether disintegrative processes, as specified by the theory, are traumatic, and whether reaching higher integration, e.g. Level IV (directed multilevel disintegration) or V (secondary integration), can be equated to posttraumatic growth.

Criticisms and Concerns

While posttraumatic growth is commonly self-reported by people from different cultures across the world, concerns have been raised on the basis that objectively measurable evidence of posttraumatic growth is limited. This has led some to question whether posttraumatic growth is real or illusory. However, biological research is finding real differences at the level of gene expression and brain activity.

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What is Empathy-Altruism?

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Introduction

Empathy-altruism is a form of altruism based on moral emotions or feelings for others.

Social exchange theory holds that in seemingly altruistic behaviour benefits to the altruist outweigh the costs the altruist bears and thus such behaviour is self-interested. In contrast, C. Daniel Batson holds that people help others in need out of genuine concern for the well-being of the other person. The key ingredient to such helping is “empathic concern”. According to Batson’s “empathy-altruism hypothesis”, if someone feels empathy towards another person, they will help them, regardless of what they can gain from it. An alternative hypothesis is “empathy-joy”, which states a person helps because they find pleasure at seeing another person experience relief. When a person does not feel empathy, the standards of social exchange theory apply.

Evidence

Debate over whether other-helping behaviour is motivated by self- or other-interest has raged between (approximately) 2000 and 2022. The prime actors in this debate included Daniel Batson, arguing for empathy-altruism, and Robert Cialdini, arguing for self-interest.

Batson recognises that people sometimes help for selfish reasons. He and his team were interested in finding ways to distinguish between motives. In one experiment, students were asked to listen to tapes from a radio programme. One of the interviews was with a woman named Carol, who talked about her bad car accident in which both of her legs were broken, her struggles and how behind she was becoming in class. Students who were listening to this particular interview were given a letter asking the student to share lecture notes and meet with her. The experimenters changed the level of empathy by telling one group to try to focus on how she was feeling (high empathy level) and the other group not to be concerned with that (low empathy level). The experimenters also varied the cost of not helping: the high cost group was told that Carol would be in their psychology class after returning to school and the low cost group believed she would finish the class at home. The results confirmed the empathy-altruism hypothesis: those in the high empathy group were almost equally likely to help her in either circumstance, while the low empathy group helped out of self-interest (seeing her in class every day made them feel guilty if they did not help).

Countering Hypotheses

Batson and colleagues set out to show that empathy motivates other-regarding helping behaviour not out of self-interest but out of true interest in the well-being of others. They addressed two hypotheses that counter the empathy-altruism hypothesis:

  • Empathy Specific Reward: Empathy triggers the need for social reward which can be gained by helping.
  • Empathy Specific Punishment: Empathy triggers the fear of social punishment which can be avoided by helping.

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What is Dopamine Supersensitivity Psychosis?

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Introduction

Dopamine supersensitivity psychosis is a hypothesis that attempts to explain the phenomenon in which psychosis (e.g. having hallucinations, which can mean hearing or seeing things that other people do not see or hear) occurs despite treatment with escalating doses of antipsychotics. Dopamine supersensitivity may be caused by the dopamine receptor D2 antagonising effect of antipsychotics, causing a compensatory increase in D2 receptors within the brain that sensitizes neurons to endogenous release of the neurotransmitter dopamine. Because psychosis is thought to be mediated—at least in part—by the activity of dopamine at D2 receptors, the activity of dopamine in the presence of supersensitivity may paradoxically give rise to worsening psychotic symptoms despite antipsychotic treatment at a given dose. This phenomenon may co-occur with tardive dyskinesia, a rare movement disorder that may also be due to dopamine supersensitivity.

Brief History

When supersensitivity psychosis was explored in 1978, a featured concern was increasing resistance to medication, requiring higher doses or not responding to higher doses. Some articles use the term tardive psychosis to reference to this specific concept. However, articles have disputed its validity. The condition has been discovered in very few people. Palmstierna asserts that tardive psychosis is a combination of “several different and not necessarily correlated phenomena related to neuroleptic treatment of schizophrenia.”

Mechanism

Dopamine supersensitivity psychosis may occur due to upregulation of dopamine 2 receptors (D2). The D2 receptor is the primary target of almost all antipsychotics, which oppose the action of the neurotransmitter dopamine at this receptor. The antagonising or “blockade” of D2 by antipsychotics may cause neurons, a type of cell within the brain, to undergo compensatory changes to make up for the loss of activity at D2 receptors. The D2 signalling pathway within neurons is complex, and involves multiple enzymes and other secondary messengers. It may be the case that, in response to antipsychotics, neurons increase the production of D2 receptors (upregulation), thereby sensitizing the neuron to dopamine. However, this is likely an oversimplification, as—despite differences in sensitivity to dopamine of around 3-fold in people that have taken antipsychotics chronically, there is a disproportionately low increase in the amount of D2 receptors in the brain in these people (around 1.4-fold in the striatum of the brain in people with schizophrenia). Other hypotheses include increases in the “active” D2 receptors (termed D2High) relative to the “inactive” conformation (D2Low).

The result is dopamine supersensitivity. It is thought that the psychotic symptoms within schizophrenia are primarily due to overactive dopamine activity in the mesolimbic area of the brain. Therefore, dopamine supersensitivity may reduce the effect of antipsychotics and increase the brain’s response to endogenous dopamine, leading to worsening psychosis.

Tardive dyskinesia, a type of rare movement disorder that can be caused by antipsychotics, may also be caused by dopamine receptor sensitization. This may explain why, for people with tardive dyskinesia, increasing the dose of the antipsychotic may temporarily improve symptoms.

Diagnosis

The original criteria for dopamine supersensitivity psychosis were the following:

A. Continuous use of antipsychotics for at least 3 months.
B. One of the following:

  1. Rebound psychosis within 6 weeks of a change (e.g. dose reduction, or antipsychotic switching) in an oral antipsychotic regimen or 3 months for long-acting injectable antipsychotics
  2. Tolerance to antipsychotic effects (requiring escalating doses, even beyond what has controlled symptoms in the past)
  3. Presence of tardive dyskinesia (which should occur when antipsychotics are withdrawn, and improve or disappear when antipsychotics are restarted)

Differential Diagnosis

It may sometimes be impossible to distinguish dopamine supersensitivity psychosis from psychosis that occurs “naturally” in the course of a primary psychotic disorder like schizophrenia, including cases in which the person was not taking their antipsychotic medication. Even in the presence of an alternative aetiology, or when it is impossible to determine the precise aetiology for a psychotic episode, it is possible that dopamine supersensitivity psychosis can play a role in the presentation. Recognising the possible role of dopamine supersensitivity psychosis in a psychotic episode has implications for how to best manage someone’s antipsychotic therapy.

Society and Culture

Dopamine supersensitivity is often dismissed as an inconsequential factor in the progression of psychotic disorders by psychiatrists in the medical literature. The dopamine supersensitivity hypothesis was discussed by investigative journalist and author Robert Whitaker in his book Anatomy of an Epidemic, published in 2010.

Research

As of 2017, much of the evidence for dopamine supersensitivity psychosis comes from studies performed in animals. There is still a need for robust, human research.

In a cohort study of people taking chronic antipsychotic therapy with either schizophrenia or schizoaffective disorder that presented for psychiatric care due to a relapse of their psychotic symptoms without a clear precipitating cause (e.g. new or worsening substance abuse, evidence of nonadherence to antipsychotics), 39% of the sample met the authors’ checklist for dopamine supersensitivity psychosis. The people that met the criteria were more likely than others to have worse symptoms when their psychosis returned (relapsed), have residual psychotic symptoms, had overall worse health outcomes at 6-month follow-ups, and were more likely to live in residential care.

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What is the British Association for Counselling and Psychotherapy?

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Introduction

The British Association for Counselling and Psychotherapy (BACP) is a professional body for counsellors and psychotherapists practising in the United Kingdom.

Brief History

Originally founded in 1977 as the British Association for Counselling, aided by a grant from the Home Office Voluntary Service Unit, it had emerged from the Standing Conference for the Advancement of Counselling. This body was inaugurated in 1970 at the instigation of the National Council for Voluntary Organisations. It was co-founded by the humanist activist Harold Blackham, and drew on detailed work Blackham had done for a non-religious counselling service for the British Humanist Association, which he led at the time. The organisation’s Chair was Nicholas Tyndall, Chief Officer at the National Marriage Guidance Council (which later become Relate).

In 1978, the headquarters were relocated from London to Rugby courtesy of the National Marriage Guidance Council which provided free accommodation to help the association establish itself. The Association is now located in Lutterworth.

In September 2000, the Association recognised that it no longer represented only those involved in counselling, but also psychotherapy, and changed its name to the British Association for Counselling and Psychotherapy.

In September 2017, the branding was refreshed introducing a new logo, colour scheme, typeface and the slogan “counselling changes lives”, based on a belief in the impact and benefits of the profession. This was Highly Commended in the 2018 memcom membership excellence awards stating that it “found success over various mediums” and “had a clear rationale for the brand relaunch and a strong proposition that counselling changes lives”.

In November 2019, the membership was reported to have surpassed 50,000, prompting the Association to share celebratory and rewarding comments from its members as a way to mark the achievement.

Governance

BACP is a company limited by guarantee and a registered charity, monitored by the Charity Commission to ensure that aims are charitable and funds used for the benefit of its members and communities in which they are active. BACP follows the Charity Commission’s Charity Governance Code as a tool for continuous improvement.

The governing instrument is the Memorandum and Articles of the Association.

The Trustees known collectively as the Board of Governors, govern the Association.

Committees

BACP operates six committees, with volunteer input, to oversee the activities of the association:

  • Audit, Risk and Performance Committee
  • Finance and Policy Committee
  • Membership and Professional Standards Committee
  • Public Protection Committee
  • Remuneration and Governance Committee
  • Research Committee

Operations

BACP works with commissioners and government to promote the counselling professions, seeking to advise and inform national and international policy and procedures concerned with counselling and psychotherapy, offering information and guidance to involved parties. BACP is consulted by government bodies, professional bodies, funding organisations, teaching institutions and many others on important issues concerning counselling and psychotherapy.

The Association sets and maintains standards for the profession. The Ethical Framework for Good Practice in Counselling and Psychotherapy along with the Professional Conduct Procedure is intended to ensure that members of BACP abide by an accepted code of conduct and accountability. The Association accredits counsellors with the appropriate training and experience via a rigorous accreditation process that requires continued education to maintain accreditation.

In October 2015, the Collaboration of the Counselling and Psychotherapy Professions (CCPP) was announced between BACP, BPC and UKCP. Whilst promising to maintain their unique differences, each organisation expressed their recognition of shared goals and a commitment to improving the nation’s mental health and wellbeing.

In June 2017, BACP presented their Female Genital Mutilation (FGM) research as a paper at the Society for Psychotherapy Research conference in Canada. Key research papers, including the FGM paper and a paper analysing data from the National Audit of Psychological Therapies, were published gold open access.

In March 2018, BACP and the SQA announced a unique partnership which promises to improve access to the counselling profession for students in Scotland through a new BACP Approved Qualification scheme.

Strategic Priorities

Following consultation with their members and stakeholders, BACP identified three key areas for particular focus where the value of counselling has the greatest potential to improve lives.

  • Older people
  • Four nations
  • Children, young people and families

Specialist Interest Divisions

BACP represent and promote specialist areas of interest within the profession by operating seven divisions, each managed by an executive committee of volunteers which run their own meetings and formulate strategies in line with BACP objectives, overseen by the BACP Board of Governors.

  • Children, young people and families
  • Healthcare
  • Workplace
  • Coaching
  • Higher and further education
  • Spiritual and pastoral
  • Private Practice

Regulation

Although counselling and psychotherapy are not statutorily regulated professions, BACP works alongside other associations to advise and appeal to government in attempts to ensure members of the public who access the counselling professions are safeguarded.

The BACP is registered for accreditation under the scheme set up by the Department of Health and regulated by the Professional Standards Authority for Health and Social Care. The Accredited status of the BACP Register is reviewed annually by the Professional Standards Authority to ensure that the highest standards are being met and good practices are being followed.

Publications

Therapy Today

The organisation’s Therapy Today magazine, with a circulation of 44,386 (ABC January-December 2016), is the most widely read specialist magazine for counsellors and psychotherapists in the UK, and has a strong international presence, publishing articles on topics crossing the breadth of counselling and psychotherapy practice, modalities and theoretical approaches.

Journals

The BACP publishes eight member-only journals:

  • Counselling and Psychotherapy Research
  • BACP Children, Young People and Families
  • BACP Workplace
  • Coaching Today
  • Healthcare Counselling and Psychotherapy
  • Private Practice
  • Thresholds
  • University and College Counselling

Notable People

  • Sue Bailey, DBE, Psychiatrist, BACP Vice-President
  • Helen Bamber, OBE, Psychotherapist, BACP Patron 2011–2016
  • Luciana Berger, Politician, BACP Vice-President
  • H.J. Blackham, Founder, and “architect of modern humanism”
  • Fiona Caldicott, DBE, Psychiatrist, former BACP President
  • Cary Cooper, CBE, Psychologist, Honorary BACP President 1976–1979
  • Derek Draper, Psychotherapist, former lobbyist and former editor of the LabourList website
  • Shreela Flather, Politician, former BACP Vice-President
  • Phillip Hodson, Journalist
  • Esther Rantzen, Television presenter, former BACP Vice-President
  • John Rowan, Psychologist
  • Diane Youdale, Psychotherapist, television personality
  • Lynne Gabriel, OBE, BACP Chair 2008-2011, BACP President 2023

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What is a Serotonin-Norepinephrine-Dopamine Reuptake Inhibitor?

Published on by Andrew MarshallLeave a comment

Introduction

A serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI), also known as a triple reuptake inhibitor (TRI), is a type of drug that acts as a combined reuptake inhibitor of the monoamine neurotransmitters serotonin, norepinephrine, and dopamine. It does this by concomitantly inhibiting the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT), respectively. Inhibition of the reuptake of these neurotransmitters increases their extracellular concentrations and, therefore, results in an increase in serotonergic, adrenergic, and dopaminergic neurotransmission. The naturally-occurring and potent SNDRI cocaine is widely used recreationally and often illegally for the euphoric effects it produces.

Other SNDRIs were developed as potential antidepressants and treatments for other disorders, such as obesity, cocaine addiction, attention-deficit hyperactivity disorder (ADHD), and chronic pain. They are an extension of selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) whereby the addition of dopaminergic action is thought to have the possibility of heightening therapeutic benefit. However, increased side effects and abuse potential are potential concerns of these agents relative to their SSRI and SNRI counterparts.

The SNDRIs are similar to non-selective monoamine oxidase inhibitors (MAOIs) such as phenelzine and tranylcypromine in that they increase the action of all three of the major monoamine neurotransmitters. They are also similar to serotonin–norepinephrine–dopamine releasing agents (SNDRAs) like MDMA (“ecstasy”) and α-ethyltryptamine (αET) for the same reason, although they act via a different mechanism and have differing physiological and qualitative effects.

Although their primary mechanisms of action are as NMDA receptor antagonists, ketamine and phencyclidine are also SNDRIs and are similarly encountered as drugs of abuse.

Indications

Depression

Major depressive disorder (MDD) is the foremost reason supporting the need for development of an SNDRI. According to the World Health Organization, depression is the leading cause of disability and the 4th leading contributor to the global burden of disease in 2000. By the year 2020, depression is projected to reach 2nd place in the ranking of DALYs (disability-adjusted life year).

About 16% of the population is estimated to be affected by major depression, and another 1% is affected by bipolar disorder, one or more times throughout an individual’s lifetime. The presence of the common symptoms of these disorders are collectively called ‘depressive syndrome’ and includes a long-lasting depressed mood, feelings of guilt, anxiety, and recurrent thoughts of death and suicide. Other symptoms including poor concentration, a disturbance of sleep rhythms (insomnia or hypersomnia), and severe fatigue may also occur. Individual patients present differing subsets of symptoms, which may change over the course of the disease highlighting its multifaceted and heterogeneous nature. Depression is often highly comorbid with other diseases, e.g. cardiovascular disease (myocardial infarction, stroke), diabetes, cancer, Depressed subjects are prone to smoking, substance abuse, eating disorders, obesity, high blood pressure, pathological gambling and internet addiction, and on average have a 15 to 30 year shorter lifetime compared with the general population.

Major depression can strike at virtually any time of life as a function of genetic and developmental pre-disposition in interaction with adverse life-events. Although common in the elderly, over the course of the last century, the average age for a first episode has fallen to ~30 years. However, depressive states (with subtly different characteristics) are now frequently identified in adolescents and even children. The differential diagnosis (and management) of depression in young populations requires considerable care and experience; for example, apparent depression in teenagers may later transpire to represent a prodromal phase of schizophrenia.

The ability to work, familial relationships, social integration, and self-care are all severely disrupted.

The genetic contribution has been estimated as 40-50%. However, combinations of multiple genetic factors may be involved because a defect in a single gene usually fails to induce the multifaceted symptoms of depression.

Pharmacotherapy

There remains a need for more efficacious antidepressant agents. Although two-thirds of patients will ultimately respond to antidepressant treatment, one-third of patients respond to placebo, and remission is frequently sub-maximal (residual symptoms). In addition to post-treatment relapse, depressive symptoms can even recur in the course of long-term therapy (tachyphylaxis). Also, currently available antidepressants all elicit undesirable side-effects, and new agents should be divested of the distressing side-effects of both first and second-generation antidepressants.

Another serious drawback of all antidepressants is the requirement for long-term administration prior to maximal therapeutic efficacy. Although some patients show a partial response within 1–2 weeks, in general one must reckon with a delay of 3–6 weeks before full efficacy is attained. In general, this delay to onset of action is attributed to a spectrum of long-term adaptive changes. These include receptor desensitization, alterations in intracellular transduction cascades and gene expression, the induction of neurogenesis, and modifications in synaptic architecture and signalling.

Depression has been associated with impaired neurotransmission of serotonergic (5-HT), noradrenergic (NE), and dopaminergic (DA) pathways, although most pharmacologic treatment strategies directly enhance only 5-HT and NE neurotransmission. In some patients with depression, DA-related disturbances improve upon treatment with antidepressants, it is presumed by acting on serotonergic or noradrenergic circuits, which then affect DA function. However, most antidepressant treatments do not directly enhance DA neurotransmission, which may contribute to residual symptoms, including impaired motivation, concentration, and pleasure.

Preclinical and clinical research indicates that drugs inhibiting the reuptake of all three of these neurotransmitters can produce a more rapid onset of action and greater efficacy than traditional antidepressants.

DA may promote neurotrophic processes in the adult hippocampus, as 5-HT and NA do. It is thus possible that the stimulation of multiple signalling pathways resulting from the elevation of all three monoamines may account, in part, for an accelerated and/or greater antidepressant response.

Dense connections exist between monoaminergic neurons. Dopaminergic neurotransmission regulates the activity of 5-HT and NE in the dorsal raphe nucleus (DR) and locus coeruleus (LC), respectively. In turn, the ventral tegmental area (VTA) is sensitive to 5-HT and NE release.

In the case of SSRIs, the promiscuity among transporters means that there may be more than a single type of neurotransmitter to consider (e.g. 5-HT, DA, NE, etc.) as mediating the therapeutic actions of a given medication. MATs are able to transport monoamines other than their “native” neurotransmitter. It was advised to consider the role of the organic cation transporters (OCT) and the plasma membrane monoamine transporter (PMAT).

To examine the role of monoamine transporters in models of depression DAT, NET, and SERT knockout (KO) mice and wild-type littermates were studied in the forced swim test (FST), the tail suspension test, and for sucrose consumption. The effects of DAT KO in animal models of depression are larger than those produced by NET or SERT KO, and unlikely to be simply the result of the confounding effects of locomotor hyperactivity; thus, these data support re-evaluation of the role that DAT expression could play in depression and the potential antidepressant effects of DAT blockade.

The SSRIs were intended to be highly selective at binding to their molecular targets. However it may be an oversimplification, or at least controversial in thinking that complex psychiatric (and neurological) diseases are easily solved by such a monotherapy. While it may be inferred that dysfunction of 5-HT circuits is likely to be a part of the problem, it is only one of many such neurotransmitters whose signalling can be affected by suitably designed medicines attempting to alter the course of the disease state.

Most common CNS disorders are highly polygenic in nature; that is, they are controlled by complex interactions between numerous gene products. As such, these conditions do not exhibit the single gene defect basis that is so attractive for the development of highly-specific drugs largely free of major undesirable side-effects (“the magic bullet”). Second, the exact nature of the interactions that occur between the numerous gene products typically involved in CNS disorders remain elusive, and the biological mechanisms underlying mental illnesses are poorly understood.

Clozapine is an example of a drug used in the treatment of certain CNS disorders, such as schizophrenia, that has superior efficacy precisely because of its broad-spectrum mode of action. Likewise, in cancer chemotherapeutics, it has been recognized that drugs active at more than one target have a higher probability of being efficacious.

In addition, the nonselective MAOIs and the TCA SNRIs are widely believed to have an efficacy that is superior to the SSRIs normally picked as the first-line choice of agents for/in the treatment of MDD and related disorders. The reason for this is based on the fact that SSRIs are safer than nonselective MAOIs and TCAs. This is both in terms of there being less mortality in the event of overdose, but also less risk in terms of dietary restrictions (in the case of the nonselective MAOIs), hepatotoxicity (MAOIs) or cardiotoxicity (TCAs).

Applications other than Depression

  • Alcoholism (c.f. DOV 102,677)
  • Cocaine addiction (e.g., indatraline)
  • Obesity (e.g., amitifadine, tesofensine)
  • Attention-deficit hyperactivity disorder (ADHD) (c.f. NS-2359, EB-1020)
  • Chronic pain (c.f. bicifadine)
  • Parkinson’s disease

List of SNDRIs

Approved Pharmaceuticals

  • Mazindol (Mazanor, Sanorex) – anorectic; 50 nM for SERT, 18 nM for NET, 45 nM for DAT
  • Nefazodone (Serzone, Nefadar, Dutonin) – antidepressant; non-selective; 200 nM at SERT, 360 nM at NET, 360 nM at DAT
  • Nefopam (Ki SER/NE/DA = 29/33/531nM)

Sibutramine (Meridia) is a withdrawn anorectic that is an SNDRI in vitro with values of 298 nM at SERT, 5451 at NET, 943 nM at DAT. However, it appears to act as a prodrug in vivo to metabolites that are considerably more potent and possess different ratios of monoamine reuptake inhibition in comparison, and in accordance, sibutramine behaves contrarily as an SNRI (73% and 54% for norepinephrine and serotonin reuptake inhibition, respectively) in human volunteers with only very weak and probably inconsequential inhibition of dopamine reuptake (16%).

Venlafaxine (Effexor) is sometimes referred to as an SNDRI, but is extremely imbalanced with values of 82 nM for SERT, 2480 nM for NET, and 7647 nM for DAT, with a ratio of 1:30:93. It may weakly inhibit the reuptake of dopamine at high doses.

Coincidental

  • Esketamine (Ketanest S) – anesthetic; S-enantiomer of ketamine; weak SNDRI action likely contributes to effects and abuse potential
  • Ketamine (Ketalar) – anesthetic and dissociative drug of abuse; weak SNDRI action likely contributes to effects and abuse potential
  • Phencyclidine (Sernyl) – discontinued anesthetic and dissociative psychostimulant drug of abuse; SNDRI action likely contributes to effects and abuse potential
  • Tripelennamine (Pyribenzamine) – antihistamine; weak SNDRI; sometimes abused for this reason
  • Mepiprazole

Undergoing Clinical Trials

  • Ansofaxine (LY03005/LPM570065). Completed Phase 2 & 3 trials. FDA accepted NDA application.
  • Centanafadine (EB-1020) – see here for details 1 to 6 to 14 ratio for NDS. Completed Phase 3 trials for ADHD.
  • OPC-64005 – In phase 2 trials (2022)
  • Lu AA37096 – see here (SNDRI and 5-HT6 modulator).
  • NS-2360 – principle metabolite of tesofensine.
  • Tesofensine (NS-2330) (2001) In trials for obesity.

Failed Clinical Trials

  • Bicifadine (DOV-220,075) (1981)
  • BMS-866,949
  • Brasofensine (NS-2214, BMS-204,756) (1995)
  • Diclofensine (Ro 8–4650) (1982)
  • DOV-216,303 (2004)
  • EXP-561 (1965)
  • Liafensine (BMS-820,836)
  • NS-2359 (GSK-372,475)
  • RG-7166 (2009–2012)
  • SEP-227,162
  • SEP-228,425
  • SEP-432 aka SEP-228432, CID:58954867
  • Amitifadine (DOV-21,947, EB-1010) (2003)
  • Dasotraline (SEP-225,289)
  • Lu AA34893 – see here (SNDRI and 5-HT2A, α1, and 5-HT6 modulator)
  • Tedatioxetine (Lu AA24530) – SNDRI and 5-HT2C, 5-HT3, 5-HT2A, and α1 modulator

Designer Drugs

  • 3-Methyl-PCPy
  • Naphyrone (O-2482, naphthylpyrovalerone, NRG-1) (2006)
  • 5-APB

Research Compounds (No Record of having been taken by Humans)

  • 3,4-Diphenylquinuclidine HCl salt: [72811-36-0].
  • 3,4-Diphenylpiperidines (a panoply of analogs was disclosed by French Hoechst) Ref: Patents: The 3′,4′-Dichloro lactam was the most powerful psychostimulant tested. Its SAR can be compared to a similar French Hoechst compound called Lomevactone.
  • MDL 47,832 [52423-89-9] Patent: SAR is similar to RG-7166 & Amitifadine. For SAR study see under Osanetant.
  • 3,3-Diphenylcyclobutanamine (1978)
  • AK Dutta: D-161 (2008) D-473 [1632000-05-5] & D-578.
  • DOV-102,677 (2006–2011)
  • Fezolamine (Win-41,528-2)
  • GlaxoSmithKline (Italia): GSK1360707F (2010): CID:46866510:
  • HP-505
  • Lundbeck group: Indatraline (1985), Lu-AA42202 & CID:11515108 [874296-10-3].
  • JNJ-7925476 (2008; first appeared in 1987), Mcn 5707 [96795-88-9] & Mcn-5292 [105234-89-7].
  • Kozikowski group: DMNPC (2000), JZ-IV-10 (2005) & JZAD-IV-22 (2010)
  • Lilly group: LR-5182 (maybe only NDRI) (1978) CID:9903806:
    • CID:11335177, CID:9867350, CID:11234430
  • HM Deutsch group: Methylnaphthidate (HDMP-28) (2001)
  • MI-4 MI-4 is the same compound as Ro-25-6981 [169274-78-6]. This is NMDA antagonist.
  • Benzazepine derivatives: SKF-83,959 (2013) & Nor-Trepipam [20569-49-7]
  • Various phenyltropanes, such as WF-23, dichloropane, and RTI-55
  • NeuroSearch group: NS9775, NS18283. & 4-Benzhydryl-1,2,3,6-tetrahydropyridine [1186529-81-6].
    • CID:54673194 (S/N/D = 0.26/6.0/4.8nM)
    • CID:9921901 [387869-25-2], 3-(3,4-Dichlorophenyl)-tropan-2-ene (S/N/D = 4.7/26/79nM)
  • Liming Shao (Sepracor/Sunovion). 3’,4’-Dichlorotramadol, CID:53321058 (S/N/D = 19/04/01nM
    • CID:66809062: CID:46870521 CID:10151573 CID:46701015
  • Takeda group, CID:44629033 (S/N/D = 11/14/190nM)
  • Trudell group: HK3-263 (S/N/D = 0.3/20/16nM)
  • Pfizer group CP-607366 & CP-939689.
    • Desmethylsertraline – active metabolite of sertraline; 76 nM for SERT, 420 nM for NET, 440 nM for DAT
    • 3,4-Dichlorotametraline (trans-(1R,4S)-sertraline) (1980)
  • Venlafaxine analogues, LPM580098 & LPM580153. And TP1 later reassigned name to PA01.
    • PRC (Carlier) group: PRC200-SS (2008), PRC050, and PRC025.
  • Albany Molecular Research group (Bruce Molino) AMR-2 (DAT 3.1nM, SERT 8.3nM, NET 3.0nM)
    • CID:49765424 (S)-enantiomer: [1254941-82-6]:
  • SK Group: CID:44555333 & CID:49866033
  • Boots UK: BTS 74,398, SPD-473 citrate: [161190-26-7]
  • Pridefine
  • SMe1EC2M3
  • SIPI5357 (CID:52939791)
  • 23j-S (S/N/D = 83/3.8/160nM)
  • Tetrazoles (ROK)
  • 10dl (CID:118713802) (S/N/D 7.6/45.2/330nM)
  • 2at (CID:118706539)
  • THIQ Derivatives: AN12 (CID:10380161): CID:9839278
  • 2j (CID:66572162) (S/N/D = 411/71/159nM)
  • 6aq (CID:70676472) (S/N/D 44/10/32nM)
  • Naphthyl milnacipran analog (2007), CID:17748230 (S/N/D = 18/05/140nM).

Herbals

  • The coca flour contains cocaine – natural alkaloid and drug of abuse
  • Ginkgo biloba extract (EGb761) – “The norepinephrine (NET), the serotonin (SERT), the dopamine (DAT) uptake transporters and MAO activity are inhibited by EGb761 in vitro”
  • St John’s Wort – natural product and over-the-counter herbal antidepressant
    • Hyperforin
    • Adhyperforin
    • Uliginosin B – IC50 DA = 90 nM, 5-HT = 252 nM, NE = 280 nM
  • Oregano extract.
  • Although not specifically a SNDRI, Rosmarinus officinalis is one of the trimonoamine modulator (TMM) that affect SER/CAs.
  • Hederagenin

Toxicological

Toxicological screening is important to ensure safety of the drug molecules. In this regard, the p m-dichloro phenyl analog of venlafaxine was dropped from further development after its potential mutagenicity was called into question.[158] The mutagenicity of this compound is still doubtful though. It was dropped for other reasons likely related to speed at which it could be released onto the market relative to the more developed compound venlafaxine. More recently, the carcinogenicity of PRC200-SS was likewise reported.

(+)-CPCA (“nocaine”) is the 3R,4S piperidine stereoisomer of (phenyltropane based) RTI-31. It is non addictive, although this might be due to it being a NDRI, not a SNDRI. The β-naphthyl analog of “Nocaine” is a SNDRI though in the case of both the SS and RR enantiomers. Consider the piperidine analogs of brasofensine and tesofensine. These were prepared by NeuroSearch (In Denmark) by the chemists Peter Moldt (2002), and Frank Wätjen (2004–2009). There are four separate isomers to consider (SS, RR, S/R and R/S). This is because there are two chiral carbon sites of asymmetry (means 2 to the power of n isomers to consider where n is the number of chiral carbons). They are therefore a diastereo(iso)meric pair of racemers. With a racemic pair of diastereomers, there is still the question of syn (cis) or anti (trans). In the case of the phenyltropanes, although there are four chiral carbons, there are only eight possible isomers to consider. This is based on the fact that the compound is bicyclic and therefore does not adhere to the equation given above.

It is complicated to explain which isomers are desired. For example, although Alan P. Kozikowski showed that R/S nocaine is less addictive than SS Nocaine, studies on variously substituted phenyltropanes by F. Ivy Carroll et at. revealed that the ββ isomers were less likely to cause convulsions, tremor and death than the corresponding trans isomers (more specifically, what is meant is the 1R,2R,3S isomers). While it does still have to be conceded that RTI-55 caused death at a dosage of 100 mg/kg, it’s therapeutic index of safety is still much better than the corresponding trans isomers because it is more potent compound.

In discussing cocaine and related compounds such as amphetamines, it is clear that these psychostimulants cause increased blood pressure, decreased appetite (and hence weight loss), increased locomotor activity (LMA) etc. In the United States, cocaine overdose is one of the leading causes of ER admissions each year due to drug overdose. People are at increased risk of heart attack and stroke and also present with an array of psychiatric symptoms including anxiety & paranoia etc. On removal of the 2C tropane bridge and on going from RTI-31 to the simpler SS and RS Nocaine it was seen that these compounds still possessed activity as NDRIs but were not powerful psychostimulants. Hence, this might be viewed as a strategy for increasing the safety of the compounds and would also be preferable to use in patients who are not looking to achieve weight loss.

In light of the above paragraph, another way of reducing the psychomotor stimulant and addictive qualities of phenyltropane stimulants is in picking one that is relatively serotonergic. This strategy was employed with success for RTI-112.

Another thing that is important and should be mentioned is the risk for serotonin syndrome when incorporating the element of 5-HT transporter inhibition into a compound that is already fully active as a NDRI (or vice versa). The reasons for serotonin syndrome are complicated and not fully understood.

Addiction

Drug addiction may be regarded as a disease of the brain reward system. This system, closely related to the system of emotional arousal, is located predominantly in the limbic structures of the brain. Its existence was proved by demonstration of the “pleasure centres,” that were discovered as the location from which electrical self-stimulation is readily evoked. The main neurotransmitter involved in the reward is dopamine, but other monoamines and acetylcholine may also participate. The anatomical core of the reward system are dopaminergic neurons of the ventral tegmentum that project to the nucleus accumbens, amygdala, prefrontal cortex and other forebrain structures.

There are several groups of substances that activate the reward system and they may produce addiction, which in humans is a chronic, recurrent disease, characterized by absolute dominance of drug-seeking behaviour.

According to various studies, the relative likelihood of rodents and non-human primates self-administering various psychostimulants that modulate monoaminergic neurotransmission is lessened as the dopaminergic compounds become more serotonergic.

The above finding has been found for amphetamine and some of its variously substituted analogues including PAL-287 etc.

RTI-112 is another good example of the compound becoming less likely to be self-administered by the test subject in the case of a dopaminergic compound that also has a marked affinity for the serotonin transporter.

WIN 35428, RTI-31, RTI-51 and RTI-55 were all compared and it was found that there was a negative correlation between the size of the halogen atom and the rate of self-administration (on moving across the series). Rate of onset was held partly accountable for this, although increasing the potency of the compounds for the serotonin transporter also played a role.

Further evidence that 5-HT dampens the reinforcing actions of dopaminergic medications comes from the co-administration of psychostimulants with SSRIs, and the phen/fen combination was also shown to have limited abuse potential relative to administration of phentermine only.

NET blockade is unlikely to play a major role in mediating addictive behaviour. This finding is based on the premise that desipramine is not self-administered, and also the fact that the NRI atomoxetine was not reinforcing. However, it was still shown to facilitate dopaminergic neurotransmission in certain brain regions such as in the core of the PFC.

Relation to Cocaine

Cocaine is a short-acting SNDRI that also exerts auxiliary pharmacological actions on other receptors. Cocaine is a relatively “balanced” inhibitor, although facilitation of dopaminergic neurotransmission is what has been linked to the reinforcing and addictive effects. In addition, cocaine has some serious limitations in terms of its cardiotoxicity due to its local anaesthetic activity. Thousands of cocaine users are admitted to emergency units in the USA every year because of this; thus, development of safer substitute medications for cocaine abuse could potentially have significant benefits for public health.

Many of the SNDRIs currently being developed have varying degrees of similarity to cocaine in terms of their chemical structure. There has been speculation over whether the new SNDRIs will have an abuse potential like cocaine does. However, for pharmacotherapeutical treatment of cocaine addiction it is advantageous if a substitute medication is at least weakly reinforcing because this can serve to retain addicts in treatment programmes:

… limited reinforcing properties in the context of treatment programs may be advantageous, contributing to improved patient compliance and enhanced medication effectiveness.

However, not all SNDRIs are reliably self-administered by animals. Examples include:

  • PRC200-SS was not reliably self-administered.
  • RTI-112 was not self-administered because at low doses the compound preferentially occupies the SERT and not the DAT.
  • Tesofensine was also not reliably self-administered by human stimulant addicts.
  • The nocaine analogue JZAD-IV-22 only partly substituted for cocaine in animals, but produced none of the psychomotor activation of cocaine, which is a trait marker for stimulant addiction.

Legality

Cocaine is a controlled drug (Class A in the UK; Schedule II in the USA); it has not been entirely outlawed in most countries, as despite having some “abuse potential” it is recognised that it does have medical uses.

Brasofensine was made “class A” in the UK under the MDA (misuse of drugs act). The semi-synthetic procedure for making BF uses cocaine as the starting material.

Naphyrone first appeared in 2006 as one of quite a large number of analogues of pyrovalerone designed by the well-known medicinal chemist P. Meltzer et al. When the designer drugs mephedrone and methylone became banned in the United Kingdom, vendors of these chemicals needed to find a suitable replacement. Mephedrone and methylone affect the same chemicals in the brain as a SNDRI, although they are thought to act as monoamine releasers and not act through the reuptake inhibitor mechanism of activity. A short time later, mephedrone and methylone were banned (which had become quite popular by the time they became illegal), naphyrone appeared under the trade name NRG-1. NRG-1 was promptly illegalised, although it is not known if its use resulted in any hospitalisations or deaths.

Role of Monoamine Neurotransmitters

Monoamine Hypothesis

The original monoamine hypothesis postulates that depression is caused by a deficiency or imbalances in the monoamine neurotransmitters (5-HT, NE, and DA). This has been the central topic of depression research for approximately the last 50 years; it has since evolved into the notion that depression arises through alterations in target neurons (specifically, the dendrites) in monoamine pathways.

When reserpine (an alkaloid with uses in the treatment of hypertension and psychosis) was first introduced to the West from India in 1953, the drug was unexpectedly shown to produce depression-like symptoms. Further testing was able to reveal that reserpine causes a depletion of monoamine concentrations in the brain. Reserpine’s effect on monoamine concentrations results from blockade of the vesicular monoamine transporter, leading to their increased catabolism by monoamine oxidase. However, not everyone has been convinced by claims that reserpine is depressogenic, some authors (David Healy in particular) have even claimed that it is antidepressant.

Tetrabenazine, a similar agent to reserpine, which also depletes catecholamine stores, and to a lesser degree 5-HT, was shown to induce depression in many patients.

Iproniazid, an inhibitor of MAO, was noted to elevate mood in depressed patients in the early 1950s, and soon thereafter was shown to lead to an increase in NA and 5-HT.

Hertting et al. demonstrated that the first TCA, imipramine, inhibited cellular uptake of NA in peripheral tissues. Moreover, both antidepressant agents were demonstrated to prevent reserpine-induced sedation. Likewise, administration of DOPA to laboratory animals was shown to reverse reserpine induced sedation; a finding reproduced in humans. Amphetamine, which releases NA from vesicles and prevents re-uptake was also used in the treatment of depression at the time with varying success.

In 1965 Schildkraut formulated the catecholamine theory of depression. This was subsequently the most widely cited article in the American Journal of Psychiatry. The theory stated that “some, if not all, depressions are associated with an absolute or relative deficiency of catecholamines, in particular noradrenaline (NA), at functionally important adrenergic receptor sites in the brain. However, elation may be associated with an excess of such amines.”

Shortly after Schildkraut’s catecholamine hypothesis was published, Coppen proposed that 5-HT, rather than NA, was the more important neurotransmitter in depression. This was based on similar evidence to that which produced the NA theory as reserpine, imipramine, and iproniazid affect the 5-HT system, in addition to the noradrenergic system. It was also supported by work demonstrating that if catecholamine levels were depleted by up to 20% but 5-HT neurotransmission remained unaltered there was no sedation in animals. Alongside this, the main observation promoting the 5-HT theory was that administration of a MAOI in conjunction with tryptophan (precursor of 5-HT) elevated mood in control patients and potentiated the antidepressant effect of MAOI. Set against this, combination of an MAOI with DOPA did not produce a therapeutic benefit.

Inserting a chlorine atom into imipramine leads to clomipramine, a drug that is much more SERT selective than the parent compound.

Clomipramine was a predecessor to the development of the more recent SSRIs. There was, in fact, a time prior to the SSRIs when selective NRIs were being considered (c.f. talopram and melitracen). In fact, it is also believed that the selective NRI nisoxetine was discovered prior to the invention of fluoxetine. However, the selective NRIs did not get promoted in the same way as did the SSRIs, possibly due to an increased risk of suicide. This was accounted for on the basis of the energising effect that these agents have. Moreover, NRIs have the additional adverse safety risk of hypertension that is not seen for SSRIs. Nevertheless, NRIs have still found uses.

Further support for the monoamine hypothesis came from monoamine depletion studies:

  • Alpha-methyl-p-tyrosine (AMPT) is a tyrosine hydroxylase enzyme inhibitor that serves to inhibit catecholamine synthesis. AMPT led to a resurgence of depressive symptoms in patients improved by the NE reuptake inhibitor (NRI) desipramine, but not by the SSRI fluoxetine. The mood changes induced by AMPT may be mediated by decreases in norepinephrine, while changes in selective attention and motivation may be mediated by dopamine.
  • Dietary depletion of the DA precursors phenylalanine and tyrosine does not result in the relapse of formerly depressed patients off their medication.
  • Administration of fenclonine (para-chlorophenylalanine) is able to bring about a depletion of 5-HT. The mechanism of action for this is via tryptophan hydroxylase inhibition. In the 1970s administration of parachlorophenylalanine produced a relapse in depressive symptoms of treated patients, but it is considered too toxic for use today.
  • Although depletion of tryptophan — the rate-limiting factor of serotonin synthesis — does not influence the mood of healthy volunteers and untreated patients with depression, it does produce a rapid relapse of depressive symptoms in about 50% of remitted patients who are being, or have recently been treated with serotonin selective antidepressants.

Dopaminergic

There appears to be a pattern of symptoms that are currently inadequately addressed by serotonergic antidepressants – loss of pleasure (anhedonia), reduced motivation, loss of interest, fatigue and loss of energy, motor retardation, apathy and hypersomnia. Addition of a pro-dopaminergic component into a serotonin based therapy would be expected to address some of these short-comings.

Several lines of evidence suggest that an attenuated function of the dopaminergic system may play an important role in depression:

  • Mood disorders are highly prevalent in pathologies characterized by a deficit in central DA transmission such as Parkinson’s disease (PD). The prevalence of depression can reach up to 50% of individuals with PD.
  • Patients taking strong dopaminergic antagonists such as those used in the treatment of psychosis are more likely than the general population to develop symptoms of depression.
  • Data from clinical studies have shown that DA agonists, such as bromocriptine, pramipexole and ropinirole, exhibit antidepressant properties.
  • Amineptine, a TCA-derivative that predominantly inhibits DA re-uptake and has minimal noradrenergic and serotonergic activity has also been shown to possess antidepressant activity. A number of studies have suggested that amineptine has similar efficacy to the TCAs, MAOIs and SSRIs. However, amineptine is no longer available as a treatment for depression due to reports of an abuse potential.
  • The B-subtype selective MAOI selegiline (a drug developed for the treatment of PD) has now been approved for the treatment of depression in the form of a transdermal patch (Emsam). For some reason, there have been numerous reports of users taking this drug in conjunction with β-phenethylamine.
  • Taking psychostimulants for the alleviation of depression is well proven strategy, although in a clinical setting the use of such drugs is usually prohibited because of their strong addiction propensity.
  • When users withdraw from psychostimulant drugs of abuse (in particular, amphetamine), they experience symptoms of depression. This is likely because the brain enters into a hypodopaminergic state, although there might be a role for noradrenaline also.

For these drugs to be reinforcing, they must block more than 50% of the DAT within a relatively short time period (<15 minutes from administration) and clear the brain rapidly to enable fast repeated administration.

In addition to mood, they may also improve cognitive performance, although this remains to be demonstrated in humans.

The rate of clearance from the body is faster for ritalin than it is for regular amphetamine.

Noradrenergic

The decreased levels of NA proposed by Schildkraut, suggested that there would be a compensatory upregulation of β-adrenoceptors. Despite inconsistent findings supporting this, more consistent evidence demonstrates that chronic treatment with antidepressants and electroconvulsive therapy (ECT) decrease β-adrenoceptor density in the rat forebrain. This led to the theory that β-adrenoceptor downregulation was required for clinical antidepressant efficacy. However, some of the newly developed antidepressants do not alter, or even increase β-adrenoceptor density.

Another adrenoceptor implicated in depression is the presynaptic α2-adrenoceptor. Chronic desipramine treatment in rats decreased the sensitivity of α2-adrenoceptors, a finding supported by the fact that clonidine administration caused a significant increase in growth hormone (an indirect measure of α2-adrenoceptor activity) although platelet studies proved inconsistent. This supersensitivity of α2-adrenoceptor was postulated to decrease locus coeruleus (the main projection site of NA in the central nervous system, CNS) NA activity leading to depression.

In addition to enhancing NA release, α2-adrenoceptor antagonism also increases serotonergic neurotransmission due to blockade of α2-adrenoceptors present on 5-HT nerve terminals.

Serotonergic

5-Hydroxytryptamine (5-HT or serotonin) is an important cell-to-cell signalling molecule found in all animal phyla. In mammals, substantial concentrations of 5-HT are present in the central and peripheral nervous systems, gastrointestinal tract and cardiovascular system. 5-HT is capable of exerting a wide variety of biological effects by interacting with specific membrane-bound receptors, and at least 13 distinct 5-HT receptor subtypes have been cloned and characterised. With the exception of the 5-HT3 receptor subtype, which is a transmitter-gated ion channel, 5-HT receptors are members of the 7-transmembrane G protein-coupled receptor superfamily. In humans, the serotonergic system is implicated in various physiological processes such as sleep-wake cycles, maintenance of mood, control of food intake and regulation of blood pressure. In accordance with this, drugs that affect 5-HT-containing cells or 5-HT receptors are effective treatments for numerous indications, including depression, anxiety, obesity, nausea, and migraine.

Because serotonin and the related hormone melatonin are involved in promoting sleep, they counterbalance the wake-promoting action of increased catecholaminergic neurotransmission. This is accounted for by the lethargic feel that some SSRIs can produce, although TCAs and antipsychotics can also cause lethargy albeit through different mechanisms.

Appetite suppression is related to 5-HT2C receptor activation as for example was reported for PAL-287 recently.

Activation of the 5-HT2C receptor has been described as “panicogen” by users of ligands for this receptor (e.g., mCPP). Antagonism of the 5-HT2C receptor is known to augment dopaminergic output. Although SSRIs with 5-HT2C antagonist actions were recommended for the treatment of depression, 5-HT2C receptor agonists were suggested for treating cocaine addiction since this would be anti-addictive. Nevertheless, the 5-HT2C is known to be rapidly downregulated upon repeated administration of an agonist agent, and is actually antagonized.

Azapirone-type drugs (e.g. buspirone), which act as 5-HT1A receptor agonists and partial agonists have been developed as anxiolytic agents that are not associated with the dependence and side-effect profile of the benzodiazepines. The hippocampal neurogenesis produced by various types of antidepressants, likewise, is thought to be mediated by 5-HT1A receptors. Systemic administration of a 5-HT1A agonist also induces growth hormone and adrenocorticotropic hormone (ACTH) release through actions in the hypothalamus.

Current Antidepressants

Most antidepressants on the market today target the monoaminergic system.

SSRIs

The most commonly prescribed class of antidepressants in the USA today are the selective serotonin reuptake inhibitors (SSRIs). These drugs inhibit the uptake of the neurotransmitter 5-HT by blocking the SERT, thus increasing its synaptic concentration, and have shown to be efficacious in the treatment of depression, however sexual dysfunction and weight gain are two very common side-effects that result in discontinuation of treatment.

Although many patients benefit from SSRIs, it is estimated that approximately 50% of depressive individuals do not respond adequately to these agents. Even in remitters, a relapse is often observed following drug discontinuation. The major limitation of SSRIs concerns their delay of action. It appears that the clinical efficacy of SSRIs becomes evident only after a few weeks.

SSRIs can be combined with a host of other drugs including bupropion, α2 adrenergic antagonists (e.g. yohimbine) as well as some of the atypical antipsychotics. The augmentation agents are said to behave synergistically with the SSRI although these are clearly of less value than taking a single compound that contains all of the necessary pharmacophoric elements relative to the consumption of a mixture of different compounds. It is not entirely known what the reason for this is, although ease of dosing is likely to be a considerable factor. In addition, single compounds are more likely to be approved by the FDA (US Food and Drug Administration) than are drugs that contain greater than one pharmaceutical ingredient (polytherapies).

A number of SRIs were under development that had auxiliary interactions with other receptors. Particularly notable were agents behaving as co-joint SSRIs with additional antagonist activity at 5-HT1A receptors. 5-HT1A receptors are located presynaptically as well as post-synaptically. It is the presynaptic receptors that are believed to function as autoreceptors (cf. studies done with pindolol). These agents were shown to elicit a more robust augmentation in the % elevation of extracellular 5-HT relative to baseline than was the case for SSRIs as measured by in vivo microdialysis.

NRIs

Norepinephrine reuptake inhibitors (NRIs) such as reboxetine prevent the reuptake of norepinephrine, providing a different mechanism of action to treat depression. However reboxetine is no more effective than the SSRIs in treating depression. In addition, atomoxetine has found use in the treatment of ADHD as a non-addictive alternative to Ritalin. The chemical structure of atomoxetine is closely related to that of fluoxetine (an SSRI) and also duloxetine (SNRI).

NDRIs

Bupropion is a commonly prescribed antidepressant that acts as a norepinephrine–dopamine reuptake inhibitor (NDRI). It prevents the reuptake of NA and DA (weakly) by blocking the corresponding transporters, leading to increased noradrenergic and dopaminergic neurotransmission. This drug does not cause sexual dysfunction or weight gain like the SSRIs but has a higher incidence of nausea. Methylphenidate is a much more reliable example of an NDRI (the action that it displays on the DAT usually getting preferential treatment). Methylphenidate is used in the treatment of ADHD; its use in treating depression is not known to have been reported, but it is presumed owing to its psychomotor activating effects and it functioning as a positive reinforcer. There are also reports of methylphenidate being used in the treatment of psychostimulant addiction, in particular cocaine addiction, since the addictive actions of this drug are believed to be mediated by the dopamine neurotransmitter.

SNRIs

Serotonin–norepinephrine reuptake inhibitors (SNRIs) such as venlafaxine (Effexor), its active metabolite desvenlafaxine (Pristiq), and duloxetine (Cymbalta) prevent the reuptake of both serotonin and norepinephrine, however their efficacy appears to be only marginally greater than the SSRIs.

Sibutramine is the name of an SNRI based appetite suppressant with use in the treatment of obesity. This was explored in the treatment of depression, but was shown not to be effective.

Both sibutramine and venlafaxine are phenethylamine-based. At high doses, both venlafaxine and sibutramine will start producing dopaminergic effects. The inhibition of DA reuptake is unlikely to be relevant at clinically approved doses.

MAOIs

Monoamine oxidase inhibitors (MAOIs) were the first antidepressants to be introduced. They were discovered entirely by serendipity. Iproniazide (the first MAOI) was originally developed as an antitubercular agent but was then unexpectedly found to display antidepressant activity.

Isoniazid also displayed activity as an antidepressant, even though it is not a MAOI. This led some people to question whether it is some property of the hydrazine, which is responsible for mediating the antidepressant effect, even going as far as to state that the MAOI activity could be a secondary side-effect. However, with the discovery of tranylcypromine (the first non-hydrazine MAOI), it was shown that MAOI is thought to underlie the antidepressant bioactivity of these agents. Etryptamine is another example of a non-hydrazine MAOI that was introduced.

The MAOIs work by inhibiting the monoamine oxidase enzymes that, as the name suggests, break down the monoamine neurotransmitters. This leads to increased concentrations of most of the monoamine neurotransmitters in the human brain, serotonin, norepinephrine, dopamine and melatonin. The fact that they are more efficacious than the newer generation antidepressants is what leads scientists to develop newer antidepressants that target a greater range of neurotransmitters. The problem with MAOIs is that they have many potentially dangerous side-effects such as hypotension, and there is a risk of food and drug interactions that can result in potentially fatal serotonin syndrome or a hypertensive crisis. Although selective MAOIs can reduce, if not eliminate these risks, their efficacy tends to be lower.

MAOIs may preferentially treat TCA-resistant depression, especially in patients with features such as fatigue, volition inhibition, motor retardation and hypersomnia. This may be a function of the ability of MAOIs to increase synaptic levels of DA in addition to 5-HT and NE. The MAOIs also seem to be effective in the treatment of fatigue associated with fibromyalgia (FM) or chronic fatigue syndrome (CFS).

Although a substantial number of MAOIs were approved in the 1960s, many of these were taken off the market as rapidly as they were introduced. The reason for this is that they were hepatotoxic and could cause jaundice.

TCAs

The first tricyclic antidepressant (TCA), imipramine (Tofranil), was derived from the antipsychotic drug chlorpromazine, which was developed as a useful antihistaminergic agent with possible use as a hypnotic sedative. Imipramine is an iminodibenzyl (dibenzazepine).

The TCAs such as imipramine and amitriptyline typically prevent the reuptake of serotonin or norepinephine.

It is the histaminiergic (H1), muscarinic acetylcholinergic (M1), and alpha adrenergic (α1) blockade that is responsible for the side-effects of TCAs. These include somnolence and lethargy, anticholinergic side-effects, and hypotension. Due to the narrow gap between their ability to block the biogenic amine uptake pumps versus the inhibition of fast sodium channels, even a modest overdose of one of the TCAs could be lethal. TCAs were, for 25 years, the leading cause of death from overdoses in many countries. Patients being treated with antidepressants are prone to attempt suicide and one method they use is to take an overdose of their medications.

Another example of a TCA is amineptine which is the only one believed to function as a DRI. It is no longer available.

Failure of SNDRIs for Depression

SNDRIs have been under investigation for the treatment of major depressive disorder for a number of years but, as of 2015, have failed to meet effectiveness expectations in clinical trials. In addition, the augmentation of a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor with lisdexamfetamine, a norepinephrine–dopamine releasing agent, recently failed to separate from placebo in phase III clinical trials of individuals with treatment-resistant depression, and clinical development was subsequently discontinued. These occurrences have shed doubt on the potential benefit of dopaminergic augmentation of conventional serotonergic and noradrenergic antidepressant therapy. As such, scepticism has been cast on the promise of the remaining SNDRIs that are still being trialled, such as ansofaxine (currently in phase II trials), in the treatment of depression. Nefazodone a weak SNDRI has been successful in treating major depressive disorder which makes it unique.

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