An Overview of Posttraumatic Growth

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 Milieu Therapy?

Introduction

Milieu therapy is a form of psychotherapy that involves the use of therapeutic communities.

Outline

Patients join a group of around 30, for between 9 and 18 months. During their stay, patients are encouraged to take responsibility for themselves and the others within the unit, based upon a hierarchy of collective consequences.

Patients are expected to hold one another to following rules, with more senior patients expected to model appropriate behaviour for newer patients. If one patient violates the rules, others who were aware of the violation but did not intervene may also be punished to varying extents based upon their involvement.

Milieu therapy is thought to be of value in treating personality disorders and behavioural problems, and can also be used with a goal of stimulating the patient’s remaining cognitive-communicative abilities.

Organisations known to use milieu therapy include Cassel Hospital, in London, Forest Heights Lodge in Evergreen, Colorado, the United States Veteran’s Administration, and the Kansas Industrial School for Girls in Beloit, Kansas.

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What is the International Expressive Arts Therapy Association?

Introduction

The International Expressive Arts Therapy Association (IEATA) is a non-profit organisation founded in 1994.

Outline

IEATA aims to encourage the “creative spirit” and supports expressive arts therapists, artists, educators, consultants and others using integrative, multi-modal arts processes for personal and community growth.

It provides:

  • A professional guild and an international network through sponsoring bi-annual conferences.
  • A global forum for dialogue, promotes guiding principles for professional practice, and works to increase recognition and use of expressive arts as a tool for psychological, physical and spiritual wellness.

Memberships

IEATA offers two kinds of registration for professional memberships.

  • “REAT” – registration is designed for those using the Expressive Arts in psychotherapy.
  • “REACE” – registration designed for expressive arts consultants and educators using the expressive arts in a broad range of approaches in education, organisational development, health fields and more.

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What is Empathy-Altruism?

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?

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 Cognitive Behavioural Analysis System of Psychotherapy?

Introduction

The cognitive behavioural analysis system of psychotherapy (CBASP) is a talking therapy, a synthesis model of interpersonal and cognitive and behavioural therapies developed by James P. McCullough Jr. of Virginia Commonwealth University specifically for the treatment of all varieties of DSM-IV chronic depression.

McCullough writes that chronic depression (i.e. depressive disorder in adults that lasts continuously for two or more years, or one year continuously in adolescents), particularly the type beginning during adolescence (early-onset), is essentially a refractory mood disorder arising from traumatic experiences or interpersonal psychological insults delivered by the patient’s significant others (nuclear or extended family).

Basic Assumptions

Absence of felt interpersonal safety in patients. Chronic mood (e.g., chronic depression) denotes an absence of felt safety as regards (a) the precipitating (original) trauma event(s) or on a less sudden and violent level, (b) maltreating-hurtful significant others who have inflicted psychological insults on the individual through interpersonal rejection, harsh punishment, censure, or emotional abandonment/neglect. The lack of felt safety (c) has been transferred to a generalized fear of interpersonal relationships.

For patients, more often than not, “people are hell” to borrow a phrase from Jean-Paul Sartre. Whether the aetiology includes sudden trauma or psychological insults, the predominant coping strategy that maintains the dysphoric mood condition is an interpersonal avoidance of persons in the home, at work, or in the social environment. The patient’s successful situational and interpersonal avoidance pattern is the major treatment issue when the chronically depressed individual enters psychotherapy.

No change is possible as long as interpersonal avoidance patterns remain. As noted above, no emotional modification or termination of the chronic depression mood is possible apart from terminating patient interpersonal avoidance by enabling them to encounter the original precipitating trauma (violent/sudden event) or the psychological insults that stem from chronic interpersonal punishment, abuse or emotional neglect. The active arena where change processes are targeted and occur in CBASP psychotherapy involves the current interpersonal milieu within which the patient functions.

Treatment Strategies

In-session focus exercises in an atmosphere of felt safety help patients confront the feared stimuli and modify the Pavlovian fear driving the refractory emotional state. Learning appropriate non-avoidant ways to deal with the fear stimuli also decreases Skinnerian avoidance behaviour and prepares the way for mood change. In the beginning of therapy, it should be remembered that the chronic mood associated with trauma or psychological insults may involve stimulus events that remain tacit knowledge (out of awareness) for patients (i.e. the pain, fear and anxiety are clearly observable but the actual precipitating and maintaining stimuli may not be clearly understood or recognised by the patient). Material derived from the Significant Other History (SOH) often illustrates the tacit knowledge dimension of the patient’s avoidance patterns. In summary, another way to describe what’s going on in the beginning of therapy is to say that patients are avoiding others (including the therapist) and not responding to the interpersonal environment. Interpersonal avoidance always dictates that the patient’s primary focus remains on himself or herself (i.e. patients stay “in their heads”). In such a psychosocial functioning state, these individuals remain helpless and hopeless and continue to respond to themselves in a solitary and never-ending circle of pain, fear, anxiety (and depression); hence, they are unable to connect with their interpersonal world in any informing way.

Therapist Role

A feature of CBASP is the interpersonal role of the psychotherapist. CBASP clinicians enact a “disciplined personal involvement role” to heal the injurious interpersonal traumas and psychological insults patients have received at the hands of harmful significant others.

Outcome Goals of Treatment and Beyond

The goals of CBASP treatment are (1) to connect patients perceptually and behaviourally to the interpersonal world they live in so that their behaviour is informed by environmental (interpersonal) influences; (2) CBASP teaches patients how to make themselves feel better emotionally as well as how to maintain affective control; (3) patients are taught to negotiate interpersonal relationships successfully which means that patients acquire the requisite skills to obtain desirable interpersonal goals; finally, patients learn the crucial importance of “maintaining” the treatment gains after psychotherapy ends. Maintaining the gains requires daily practice of the in-session learning which protects (perpetuates) the extinction of the old pathological patterns of behaviour. Post-therapy practice for the rest of their lives holds in abeyance the ever-present danger of relapse and recurrence.

Combination Treatment

A large-scale study, published in 2000 by Martin Keller of Brown Medical School and others, compared the (then available) antidepressant Serzone (aka Nefazodone) with CBASP. Six hundred and eighty-one patients with severe chronic depression (some with other psychiatric illnesses) were enrolled in the trial, and were assigned to either Serzone, CBASP, or combination Serzone-CBASP for 12 weeks. The response rates to either Serzone or CBASP alone were 55 percent and 52 percent, respectively, for the 76 percent who completed the study. In other words, a little more than half of the completers in those two arms of the trial reduced their depression by 50 percent or better.

The Serzone findings roughly correspond with many other trial results for antidepressants, and underscore a major weakness in these drugs—that while they are effective, the benefit is often marginal and the treatment outcome problematic. Similarly, the CBASP findings validate other studies finding talking therapy about equal in efficacy to taking antidepressants.

The results for the combination drug-therapy group, however, were surprising, with 85% of the completing patients achieving a 50 percent reduction in symptoms or better. 42% in the combination group achieved remission (a virtual elimination of all depressive symptoms) compared to 22% in the Serzone group and 24% in the CBASP group.

The authors of the frequently cited study noted that “the rates of response and remission in the combined-treatment group were substantially higher than those that might have been anticipated on the basis of the outcomes of previous trials in similar patients.” Their figures show that treating depression with a combination of both an anti-depressant drug and a form of cognitive behaviour therapy can be highly effective, giving substantially better results than other methods of dealing with depression.

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What is the British Association for Counselling and Psychotherapy?

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 Adaptive Mentalisation-Based Integrative Treatment?

Introduction

Adaptive mentalisation-based integrative treatment (AMBIT) is a novel adaptation (by Dickon Bevington, Peter Fuggle, Liz Cracknell, Peter Fonagy, Eia Asen, Mary Target, Neil Dawson and Rabia Malik) of the theory of mentalisation and practices of mentalisation-based treatment to address the needs of chaotic, complex and multiply comorbid youth, via team-based (predominantly outreach) multimodal practices.

Background

Previously called “Adolescent Mentalisation Based Integrative Treatment”, AMBIT changed its name to “Adaptive…” in recognition of the fact that it is now being used by a wide range of teams across the UK and internationally, that extend beyond the adolescent age range (adults with severe and enduring relational difficulties, families with children where there are safeguarding concerns, young adults, etc.) Adaptation is also at the heart of AMBIT, which encourages local teams to adapt, build upon, and share these adaptations to its core components; AMBIT aspires to be an Open-source model of therapy innovation. This name change was recognised a book published by Oxford University Press (Bevington, D., Fuggle, P., Cracknell, L., and Fonagy, P. “Adaptive Mentalization Based Integrative Treatment: a guide for teams to develop systems of care” OUP 2017).

These practices, shaped by an eightfold principled therapeutic stance and using mentalization as the integrating framework, balance the development of a strong therapeutic attachment to a key worker with strong peer-to-peer relationships between workers that are designed counteract the potential for destabilising effects from such intense work.

Mentalization is applied and fostered explicitly in four directions in AMBIT:

  • Towards the young person and their family/carers.
  • Towards colleagues and peers at the level of the team.
  • Towards the wider multi-agency network.

In addition, a range of manualized ‘barefoot’ adaptations of existing evidence-based treatment modalities are available to workers, but the approach also encourages the development of a culture of team-based reflection upon practice and outcomes, of learning, and of sharing. This has much in common with the notion of a “learning organisation” stance (see the work of Peter Senge) within local teams, but AMBIT includes the promotion of constrained and disciplined approaches to the local adaptation of each team’s own wiki-based practice manual. These wikis come to represent specific local implementations that offer a “fit” for local cultures and service ecologies. The collaborative disciplines around their adaptation is a practice referred to as “manualisation”; manualisation is seen as analogous to mentalisation at the level of the team (making sense of “why we practice in this way in that kind of situation”, and broadcasting this transparently, with a view to improving this current understanding through feedback.)

Treatment Manual

AMBIT deploys an open-source wiki-based approach to treatment manualisation based on TiddlyWiki; a server-side hosting platform allows multiple teams to develop their own locally adapted versions, each drawing on a shared common core of AMBIT material. Drawing on developments in programming, the authors have described the approach as an “open source approach to therapy”.

Implementations

As at March 2018, approximately 200 teams around the UK and internationally have been trained in AMBIT by the AMBIT programme based at the Anna Freud National Centre for Children and Families charity in London. Encouraging early outcomes evaluative evidence has been published, but as a novel approach there are as yet no completed randomised controlled trials.

Independent Reviews, Awards and Sponsors

AMBIT is described in a number of independent reviews, including a 2018 review on “Psychotherapeutic interventions and contemporary developments: common and specific factors” in the BJPsych Advances journal. It is described in Chapter 42 of the 3rd edition of Child Psychology and Psychiatry Frameworks for Clinical Training and Practice and in a review by the Youth Justice Working Group (2012), the Centre for Mental Health (2010) and in a literature review on integrative psychotherapy for children and adolescents by Krueger and Glass.

The AMBIT Collaboration was awarded the “Innovation Nation” award for Innovation in Collaboration from The Guardian newspaper and Virgin Business Media in 2012.

AMBIT has been supported by grants from Comic Relief, the City Bridge Trust and the James Wentworth Stanley Memorial Fund.

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What is a Serotonin-Norepinephrine-Dopamine Reuptake Inhibitor?

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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What is Excitotoxicity?

Introduction

In excitotoxicity, nerve cells suffer damage or death when the levels of otherwise necessary and safe neurotransmitters such as glutamate become pathologically high, resulting in excessive stimulation of receptors. For example, when glutamate receptors such as the NMDA receptor or AMPA receptor encounter excessive levels of the excitatory neurotransmitter, glutamate, significant neuronal damage might ensue. Excess glutamate allows high levels of calcium ions (Ca2+) to enter the cell. Ca2+ influx into cells activates a number of enzymes, including phospholipases, endonucleases, and proteases such as calpain. These enzymes go on to damage cell structures such as components of the cytoskeleton, membrane, and DNA. In evolved, complex adaptive systems such as biological life it must be understood that mechanisms are rarely, if ever, simplistically direct. For example, NMDA in subtoxic amounts induces neuronal survival of otherwise toxic levels of glutamate.

Excitotoxicity may be involved in cancers, spinal cord injury, stroke, traumatic brain injury, hearing loss (through noise overexposure or ototoxicity), and in neurodegenerative diseases of the central nervous system such as multiple sclerosis, Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), Parkinson’s disease, alcoholism, alcohol withdrawal or hyperammonaemia and especially over-rapid benzodiazepine withdrawal, and also Huntington’s disease. Other common conditions that cause excessive glutamate concentrations around neurons are hypoglycaemia. Blood sugars are the primary glutamate removal method from inter-synaptic spaces at the NMDA and AMPA receptor site. Persons in excitotoxic shock must never fall into hypoglycaemia. Patients should be given 5% glucose (dextrose) IV drip during excitotoxic shock to avoid a dangerous build up of glutamate around NMDA and AMPA neurons. When 5% glucose (dextrose) IV drip is not available high levels of fructose are given orally. Treatment is administered during the acute stages of excitotoxic shock along with glutamate antagonists. Dehydration should be avoided as this also contributes to the concentrations of glutamate in the inter-synaptic cleft and “status epilepticus can also be triggered by a build up of glutamate around inter-synaptic neurons.”

Refer to Neuroprotection.

Brief History

The harmful effects of glutamate on the central nervous system were first observed in 1954 by T. Hayashi, a Japanese scientist who stated that direct application of glutamate caused seizure activity, though this report went unnoticed for several years. D.R. Lucas and J.P. Newhouse, after noting that “single doses of [20–30 grams of sodium glutamate in humans] have … been administered intravenously without permanent ill-effects”, observed in 1957 that a subcutaneous dose described as “a little less than lethal”, destroyed the neurons in the inner layers of the retina in newborn mice. In 1969, John Olney discovered that the phenomenon was not restricted to the retina, but occurred throughout the brain, and coined the term excitotoxicity. He also assessed that cell death was restricted to postsynaptic neurons, that glutamate agonists were as neurotoxic as their efficiency to activate glutamate receptors, and that glutamate antagonists could stop the neurotoxicity.

In 2002, Hilmar Bading and co-workers found that excitotoxicity is caused by the activation of NMDA receptors located outside synaptic contacts. The molecular basis for toxic extrasynaptic NMDA receptor signalling was uncovered in 2020 when Hilmar Bading and co-workers described a death signalling complex that consists of extrasynaptic NMDA receptor and TRPM4. Disruption of this complex using NMDAR/TRPM4 interface inhibitors (also known as ‚interface inhibitors‘) renders extrasynaptic NMDA receptor non-toxic.

Pathophysiology

Excitotoxicity can occur from substances produced within the body (endogenous excitotoxins). Glutamate is a prime example of an excitotoxin in the brain, and it is also the major excitatory neurotransmitter in the central nervous system of mammals. During normal conditions, glutamate concentration can be increased up to 1mM in the synaptic cleft, which is rapidly decreased in the lapse of milliseconds. When the glutamate concentration around the synaptic cleft cannot be decreased or reaches higher levels, the neuron kills itself by a process called apoptosis.

This pathologic phenomenon can also occur after brain injury and spinal cord injury. Within minutes after spinal cord injury, damaged neural cells within the lesion site spill glutamate into the extracellular space where glutamate can stimulate presynaptic glutamate receptors to enhance the release of additional glutamate. Brain trauma or stroke can cause ischemia, in which blood flow is reduced to inadequate levels. Ischemia is followed by accumulation of glutamate and aspartate in the extracellular fluid, causing cell death, which is aggravated by lack of oxygen and glucose. The biochemical cascade resulting from ischemia and involving excitotoxicity is called the ischemic cascade. Because of the events resulting from ischemia and glutamate receptor activation, a deep chemical coma may be induced in patients with brain injury to reduce the metabolic rate of the brain (its need for oxygen and glucose) and save energy to be used to remove glutamate actively. (The main aim in induced comas is to reduce the intracranial pressure, not brain metabolism).

Increased extracellular glutamate levels leads to the activation of Ca2+ permeable NMDA receptors on myelin sheaths and oligodendrocytes, leaving oligodendrocytes susceptible to Ca2+ influxes and subsequent excitotoxicity. One of the damaging results of excess calcium in the cytosol is initiating apoptosis through cleaved caspase processing. Another damaging result of excess calcium in the cytosol is the opening of the mitochondrial permeability transition pore, a pore in the membranes of mitochondria that opens when the organelles absorb too much calcium. Opening of the pore may cause mitochondria to swell and release reactive oxygen species and other proteins that can lead to apoptosis. The pore can also cause mitochondria to release more calcium. In addition, production of adenosine triphosphate (ATP) may be stopped, and ATP synthase may in fact begin hydrolysing ATP instead of producing it, which is suggested to be involved in depression.

Inadequate ATP production resulting from brain trauma can eliminate electrochemical gradients of certain ions. Glutamate transporters require the maintenance of these ion gradients to remove glutamate from the extracellular space. The loss of ion gradients results in not only the halting of glutamate uptake, but also in the reversal of the transporters. The Na+-glutamate transporters on neurons and astrocytes can reverse their glutamate transport and start secreting glutamate at a concentration capable of inducing excitotoxicity. This results in a buildup of glutamate and further damaging activation of glutamate receptors.

On the molecular level, calcium influx is not the only factor responsible for apoptosis induced by excitoxicity. Recently, it has been noted that extrasynaptic NMDA receptor activation, triggered by both glutamate exposure or hypoxic/ischemic conditions, activate a CREB (cAMP response element binding) protein shut-off, which in turn caused loss of mitochondrial membrane potential and apoptosis. On the other hand, activation of synaptic NMDA receptors activated only the CREB pathway, which activates BDNF (brain-derived neurotrophic factor), not activating apoptosis

Exogenous Excitotoxins

Exogenous excitotoxins refer to neurotoxins that also act at postsynaptic cells but are not normally found in the body. These toxins may enter the body of an organism from the environment through wounds, food intake, aerial dispersion etc. Common excitotoxins include glutamate analogues that mimic the action of glutamate at glutamate receptors, including AMPA and NMDA receptors.

BMAA

The L-alanine derivative β-methylamino-L-alanine (BMAA) has long been identified as a neurotoxin which was first associated with the amyotrophic lateral sclerosis/parkinsonism–dementia complex (Lytico-bodig disease) in the Chamorro people of Guam. The widespread occurrence of BMAA can be attributed to cyanobacteria which produce BMAA as a result of complex reactions under nitrogen stress.

Following research, excitotoxicity appears to be the likely mode of action for BMAA which acts as a glutamate agonist, activating AMPA and NMDA receptors and causing damage to cells even at relatively low concentrations of 10 μM.[31] The subsequent uncontrolled influx of Ca2+ then leads to the pathophysiology described above. Further evidence of the role of BMAA as an excitotoxin is rooted in the ability of NMDA antagonists like MK801 to block the action of BMAA. More recently, evidence has been found that BMAA is mis-incorporated in place of L-serine in human proteins. A considerable portion of the research relating to the toxicity of BMAA has been conducted on rodents. A study published in 2016 with vervets (Chlorocebus sabaeus) in St. Kitts, which are homozygous for the apoE4 (APOE-ε4) allele (a condition which in humans is a risk factor for Alzheimer’s disease), found that vervets orally administered BMAA developed hallmark histopathology features of Alzheimer’s Disease including amyloid beta plaques and neurofibrillary tangle accumulation. Vervets in the trial fed smaller doses of BMAA were found to have correlative decreases in these pathology features. This study demonstrates that BMAA, an environmental toxin, can trigger neurodegenerative disease as a result of a gene/environment interaction.

While BMAA has been detected in brain tissue of deceased ALS/PDC patients, further insight is required to trace neurodegenerative pathology in humans to BMAA.

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