What is Stilted Speech?

Introduction

In psychiatry, stilted speech or pedantic speech is communication characterised by situationally-inappropriate formality (refer to Communication Deviance). This formality can be expressed both through abnormal prosody as well as speech content that is “inappropriately pompous, legalistic, philosophical, or quaint”. Often, such speech can act as evidence for autism spectrum disorder (ASD) or a thought disorder, a common symptom in schizophrenia or schizotypal personality disorder.

To diagnose stilted speech, researchers have previously looked for the following characteristics:

  • Speech conveying more information than necessary.
  • Vocabulary and grammar expected from formal writing rather than conversational speech.
  • Unneeded repetition or corrections.

While literal and long-winded word content is often the most identifiable feature of stilted speech, such speech often displays irregular prosody, especially in resonance. Often, the loudness, pitch, rate, and nasality of pedantic speech vary from normal speech, resulting in the perception of pedantic or stilted speaking. For example, overly loud or high-pitched speech can come across to listeners as overly forceful while slow or nasal speech creates an impression of condescension.

These attributions, which are commonly found in patients with ASD, partially account for why stilted speech has been considered a diagnostic criterion for the disorder. Stilted speech, along with atypical intonation, semantic drift, terseness, and perseveration, are all qualities known to be commonly impaired during conversation with adolescents on the autistic spectrum. Often, stilted speech found in children with ASD will also be especially stereotypic or rehearsed.

Patients with schizophrenia are also known to experience stilted speech. This symptom is attributed to both an inability to access more commonly used words and a difficulty understanding pragmatics – the relationship between language and context. However, stilted speech appears as a less common symptom compared to a certain number of other symptoms of the psychosis. This element of cognitive disorder is also exhibited as a symptom in the narcissistic personality disorder.

There is disagreement on the definition of psychophenomenology within the discipline of psychiatry, e.g. published sources provide definitions that are “various and sometimes conflicting (Rule 2005)”.

What is Communication Deviance?

Introduction

Communication deviance (CD) occurs when a speaker fails to effectively communicate meaning to their listener with confusing speech patterns or illogical patterns.

Refer to Stilted Speech.

Background

These disturbances can range from vague linguistic references, contradictory statements to more encompassing non-verbal problems at the level of turn-taking.

The term was originally introduced by Lyman Wynne and Margaret Singer in 1963 to describe a communication style found among parents who had children with schizophrenia. According to Wynne, people are able to focus their attention and identify meaning from external stimuli beginning with their interactions, particularly with their parents, during their early years of life. In family communication, deviance is present in the way members acknowledge or affirm one another as well as in task performance.

A recent meta-analysis reported that communication deviance is highly prevalent in parents of patients diagnosed with schizophrenia and adoption studies have reported significant associations between CD in the parent and thought disorder in the offspring, however, the mechanisms by which CD impacts on the offspring’s cognition are still unknown. Some researchers theorize that, in the case of a high degree of egocentric communication in parents where the sender and the receiver do not speak and listen according to each other’s premises, the child develops uncertainty.

The research of psychiatrists and psychoanalysts Lyman Wynne and Theodore Lidz on communication deviance and roles (e.g. pseudo-mutuality, pseudo-hostility, schism and skew) in families of people with schizophrenia also became influential with systems-communications-oriented theorists and therapists.

What was Disorganised Schizophrenia?

Introduction

Disorganised schizophrenia, or hebephrenia, was a subtype of schizophrenia prior to 2013. Subtypes of schizophrenia were no longer recognised as separate conditions in DSM 5 published in 2013. The disorder is no longer listed in the 11th revision of the International Classification of Diseases (ICD-11).

Disorganised schizophrenia is classified within ICD-10 the existing classification, in practice, until the 01 January 2022, as a mental and behavioural disorder, because the classification was thought to be an extreme expression of the disorganisation syndrome that has been hypothesized to be one aspect of a three-factor model of symptoms in schizophrenia, the other factors being reality distortion (involving delusions and hallucinations) and psychomotor poverty (lack of speech, lack of spontaneous movement and various aspects of blunting of emotion).

Presentation

The condition is also known as hebephrenia, named after the Greek term for “adolescence” – ἥβη (hḗbē) – and possibly the ancient-Greek goddess of youth, Hebe, daughter of Hera. The term refers to the ostensibly more prominent appearance of the disorder in persons around puberty.

The prominent characteristics of this form are disorganised behaviour and speech (see formal thought disorder), including loosened associations and schizophasia (“word salad”), and flat or inappropriate affect. In addition, psychiatrists must rule out any possible sign of catatonic schizophrenia.

The most prominent features of disorganised schizophrenia are not delusions and hallucinations, as in paranoid schizophrenia, although fragmentary delusions (unsystemised and often hypochondriacal) and hallucinations may be present. A person with disorganised schizophrenia may also experience behavioural disorganisation, which may impair his or her ability to carry out daily activities such as showering or eating.

The emotional responses of such people often seem strange or inappropriate. Inappropriate facial responses may be common, and behaviour is sometimes described as “silly”, such as inappropriate laughter. Sometimes, there is a complete lack of emotion, including anhedonia (lack of pleasure), and avolition (lack of motivation). Some of these features are also present in other types of schizophrenia, but they are most prominent in disorganised schizophrenia.

Treatment

This form of schizophrenia is typically associated with early onset (often between the ages of 15 and 25 years) and is thought to have a poor prognosis because of the rapid development of negative symptoms and decline in social functioning.

Use of electroconvulsive therapy has been proposed; however, the effectiveness after treatment is in question.

What is the Kiddie Schedule for Affective Disorders and Schizophrenia?

Introduction

The Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS) is a semi-structured interview aimed at early diagnosis of affective disorders such as depression, bipolar disorder, and anxiety disorder. There are currently four different versions of the test that are structured to include interviews with both the child and the parents or guardians.

The K-SADS serves to diagnose childhood mental disorders in school-aged children 6-18. The different adaptations of the K-SADS were written by different researchers and are used to screen for many affective and psychotic disorders. Versions of the K-SADS are semi-structured interviews administered by health care providers or highly trained clinical researchers, which gives more flexibility to the interviewer about how to phrase and probe items, while still covering a consistent set of disorders. Due to its semi-structured interview format, time to complete the administration varies based on the youth/adult being interviewed. Most versions of the K-SADS also include “probes”, if these are endorsed, another diagnostic category will be reviewed. If the probe is not endorsed, additional symptoms for that particular disorder will not be queried.

The K-SADS has been found to be reliable and valid in multiple research and treatment settings.

Refer to the Schedule for Affective Disorders and Schizophrenia (SADS).

Development and Brief History

The Schedule for Affective Disorders and Schizophrenia for School Aged Children, or K-SADS, was originally created as an adapted version of the Schedule for Affective Disorders and Schizophrenia, a measure for adults. The K-SADS was written by Chambers, Puig-Antich, et al. in the late 1970s. The K-SADS was developed to promote earlier diagnosis of affective disorders and schizophrenia in children in a way that incorporates reports by both the child and parent and a “summary score” by the interviewer based on observations and teacher ratings.

The first version of the K-SADS differed from other tests on children because it relied on answers to interview questions rather than observances during games and interactions. The 1990s led to the creation of different versions of the K-SADS for different purposes, such as ascertaining lifetime diagnoses (K-SADS-E) or focusing on current episodes (K-SADS-P).

Versions

KSADS-Present Version (KSADS-P)

The KSADS-P was the first version of the K-SADS, developed by Chambers and Puig-Antich in 1978 as a version of the Schedule for Affective Disorders and Schizophrenia adapted for use with children and adolescents 6-19 years old. This version rephrased the SADS to make the wording of the questionnaire pertain to a younger age group. For example, mania symptoms in children might be manifest differently than in adulthood (e.g. children might have not have the same opportunity to spend money impulsively, nor would they likely have access to credit cards or checking accounts; instead, they might give away all their favourite toys or empty their parent’s wallet to gain spending money). The KSADS-P is a structured interview given by trained clinicians or clinical researchers who interview both the child and the parent. This original version assesses symptoms that have occurred in the most current episode (within the week preceding the interview), as well as symptoms that have occurred within the last 12 months. The KSADS-P has many limitations: it does not assess lifetime symptoms and history, does not include many psychiatric diagnoses of interest in childhood (such as autistic spectrum disorders), and does not include diagnosis specific impairment ratings.

KSADS-Present and Lifetime Version (KSADS-PL)

The K-SADS-PL is used to screen for affective and psychotic disorders as well as other disorders, including, but not limited to Major Depressive Disorder, Mania, Bipolar Disorders, Schizophrenia, Schizoaffective Disorder, Generalized Anxiety, Obsessive Compulsive Disorder, Attention Deficit Hyperactivity Disorder, Conduct Disorder, Anorexia Nervosa, Bulimia, and Post-Traumatic Stress Disorder. This semi-structured interview takes 45-75 minutes to administer. It was written by Joan Kaufman, Boris Birmaher, David Brent, Uma Rao, and Neal Ryan. The majority of items in the K-SADS-PL are scored using a 0-3 point rating scale. Scores of 0 indicate no information is available; scores of 1 suggest the symptom is not present; scores of 2 indicate sub-threshold presentation and scores of 3 indicate threshold presentation of symptoms. The KSADS-PL has six components:

ComponentDescription
Unstructured Introductory Interview – Developmental HistoryThe first part of the interview asks about developmental history and the history of the presenting problem. The interviewer takes detailed notes on the record sheet. Prompts cover basic demographic information, physical and mental health history and prior treatments, current complaints, and the youth’s relations with friends, family, school, and hobbies. This section allows flexibility for the interviewer to collect more information on questions that need elaboration.
Diagnostic Screening InterviewThe diagnostic screening interview reviews the most severe current and past symptoms. There are probes and scoring criteria for each symptom presented. Symptoms of disorders are grouped into modules. If the patient does not display any current or past symptoms for the screening questions, then the rest of the module’s questions do not need to be asked.
Completion Checklist SupplementA supplemental checklist is used to screen for additional disorders.
Appropriate Diagnostic SupplementsThese supplements review presence/absence of symptoms for other disorders, including anxiety disorders, behavioural disorders, and substance abuse.
Summary Lifetime Diagnosis ChecklistBased on the previous sections, this section summarises which disorders have been present from first episode to now.
Children’s Global Assessment Scale (C-GAS)Scores the child’s level of functioning.

KSADS-Epidemiological (KSADS-E)

The KSADS-E, which is the epidemiological version of the KSADS, is a tool to interview parents about possible psychopathology in children from preschool onward. It was developed by Puig-Antich, Orvaschel, Tabrizi, and Chambers in 1980 as a structured interview. The tool examines both past and current episodes, focusing on the most severe past episode and the most current episode. However, this tool does not rate symptom severity; it should only be used to assess presence or absence of symptomatology. This version of the K-SADS introduced screening questions, which, if negative, allowed skipping the remaining diagnostic probes. Furthermore, the K-SADS-E also includes “skip out” criteria when assessing other diagnostic disorders (ADHD, PTSD, etc.), allowing those that screen positive to immediately be interviewed for all of the symptoms regarding that diagnosis, and those that screened negative could “skip out” of being interviewed on the remaining symptoms.

WASH-U-KSADS

The WASH-U version of the K-SADS was written by Barbara Geller and colleagues in 1996. It is a modified version of the 1986 K-SADS. This version is like many other versions of the K-SADS in that it is semi-structured, administered by clinicians to both parent and child separately, and assesses present episodes. However, this version specifically expands the mania section in order to be more applicable to pre-pubertal mania. In particular, it queries presence/absence of rapid cycling. It also includes a section on multiple other DSM-IV diagnoses, and examines both present and lifetime symptoms as well as symptom onset and offset items. These modifications made this specific version particularly useful for phenomenology studies.

KSADS Mania Rating Scale (KMRS) and Depression Rating Scale (KDRS)
It also is possible to use the items in the mania and depression modules of some versions of the KSADS to get an interview-based rating of the severity of mood problems. The KMRS and KDRS use a 1 to 6 rating format (the same as in the WASH-U, -P, and PL-Plus versions). Adding up the items provides a measure of the total symptom burden. The KMRS assess 21 symptoms related to mania, hypomania, and rapid cycling. Each item is rated on a 0-6 rating scale. Scores of 0 suggest no information is available (missing data); scores of 1 suggest the symptom is not present at all; scores of 2 suggest the symptom is slightly present; scores of 3 suggest the symptom is mildly severe; scores of 4 suggest the symptom is moderately severe; scores of 5 suggest the symptom is severe; and scores of 6 suggest the symptom is extremely severe. Items with scores of 4 or higher are clinically significant/problematic. Trained clinicians or clinical researchers administer the assessment to both the child and the parent, which each provide their own separate score for each item (P and C), and the total score encompasses the sum of all of the items (S).

The KMRS is an alternative to the Young Mania Rating Scale designed by Young et al. (frequently referred to as the YMRS). The YMRS is more well-known and widely used, but because it was written in 1978, it does not include all of the symptoms of mania from ICD-9 or ICD-10 (nor DSM-IV or DSM-5), as it predated them all. The YMRS was also designed for completion by nurses at the end of their eight-hour shift on an inpatient unit, observing adult patients. The KMRS has several advantages in comparison: It covers all the symptoms used in current versions of ICD and DSM, it was designed for use with children and teenagers, and it was written and validated as an interview. Studies have found excellent internal consistency and inter-rater reliability, as well as exceptionally high correlation with the YMRS. Similarly, the KDRS would be analogous to the Child Depression Rating Scale-Revised. The CDRS-R was also designed to be done as an interview, but the item content predates the current ICD and DSM and omits some important symptoms. The KDRS also shows strong reliability (internal consistency and inter-rater) and exceptionally high correlations with the KDRS.

Impact

The K-SADS is used to measure previous and current symptoms of affective, anxiety, psychotic, and disruptive behaviour disorders. The K-SADS has become one of the most widely used diagnostic interviews in research, particular for projects focused on mood disorders.

The K-SADS-PL has been written and translated into 16 different languages, including Korean, Hebrew, Turkish, Icelandic, and Persian. The K-SADS-PL is also available in several Indian dialects including Kannada, Marathi, Tamil and Telugu.

Limitations

One limitation of the K-SADS is that it requires extensive training to give properly, including observation techniques, score calibration, and re-checks to test inter-rater reliability.

What is SANE (Charity)?

Introduction

SANE is a UK mental health charity working to improve quality of life for people affected by mental illness.

Brief History

SANE was established in 1986 to improve the quality of life for people affected by mental illness, following the overwhelming public response to a series of articles published in The Times entitled “The Forgotten Illness”. Written by the charity’s founder and Chief Executive, Marjorie Wallace, the articles exposed the neglect of people suffering from mental illness and the poverty of services and information for individuals and families. From its initial focus on schizophrenia (the name started as an acronym for “Schizophrenia: A National Emergency”), SANE expanded and is now concerned with all mental illnesses. SANE’s vision has been to raise public awareness, instigate research, and bring more effective professional treatment and compassionate care to everyone affected by mental illness.

During the COVID-19 pandemic lockdowns, SANE’s hotline received a 200% increase in calls.

Aims and Outcomes

SANE uses the Charities Evaluation Services framework to assess its work. They have three organisational aims:

  • Reducing the impact of mental illness.
  • Improving treatment and care by increasing knowledge about mental illness.
  • Influencing policy and public attitudes by increasing understanding of mental illness.

These aims are connected to a number of specific outcomes which are used to monitor and evaluate SANE’s work.

Objectives

SANE works to:

  • Raise awareness and combat stigma about mental illness, educating and campaigning to improve mental health services.
  • Provide care and emotional support for people with mental health problems, their families and carers as well as information for other organisations and the public.
  • Initiate research into the causes and treatments of serious mental illness such as schizophrenia and depression and the psychological and social impact of mental illness.

Online Forum

One of the many features of SANE’s website is the Support Forum – a peer to peer community, moderated by SANE. The Support Forum provides a space where people affected by mental illness, family, friends and carers can offer and receive mutual support at any time of day or night 365 days a year. Users of the Support Forum share thoughts, feelings and experiences of the difficulties and challenges that can arise from living with mental illness. The forum has several different discussion rooms including:

  • Newbies.
  • Family, Friends and Carers.
  • Information Exchange.
  • Creative Corner.
  • Rant Room.

Marie talked about her experience of using the Support Forum: “I was scared to tell anyone how I was feeling, so I used the Support Forum at first. There I found a community of other sufferers and realised I wasn’t alone. I can’t express how pleased I was – I had felt so isolated up until that point.”

Emotional Support

SANE offers emotional support and information to anyone affected by mental health problems through helpline (SANEline) and text (Textcare) services and an online Support Forum where people share their feelings and experiences.

These services are led by SANE’s team of mental health professionals and delivered by a force of over 140 volunteers who undergo rigorous training and in many cases give hundreds of hours of their free time each year. SANE’s Caller Care programme provides call-back to give on-going support and help people alleviate a crisis phase or get through difficult circumstances.

Research

SANE undertakes neuroscience research to understand the causes of serious mental illness. SANE opened the Prince of Wales International Centre (POWIC) for SANE Research in 2003 to focus this work and establish a home for multi-disciplinary research. SANE provides space within POWIC to the Oxford Mindfulness Centre, which provides Mindfulness-based cognitive therapy training, integrating brain research with meditation techniques, and Professor Daniel Freeman.

SANE’s psychosocial research team focuses on the social and psychological aspects of mental illness impacting service users, carers and mental health professionals.

Campaigns

SANE campaigns to influence mental health policy and improve services, as well as combating the stigma and ignorance, which all too often exacerbate the distress that people experience. Previous work includes; campaigning for reform of mental health law, campaigning for better access to psychological therapies and campaigning about the unacceptable standard of care on many psychiatric wards.

Black Dog Campaign

In 2011, to mark its 25th anniversary, SANE launched the Black Dog Campaign. The campaign aimed to increase awareness and understanding of depression and other mental illness, to introduce new emotional support services, and encourage more people to seek help.

The Black Dog has been used as a metaphor for depression from antiquity to the present day. To bring the campaign to life SANE designed Black Dog statues that were placed across London and other major UK cities to raise awareness, reduce stigma and misunderstanding of mental health problems and to encourage more people to seek help.

It was hoped that the physical presence of a Black Dog would help people define their experience of the “invisible” condition that characterises mental illness, as well as promoting more open discussion, understanding and acceptance. In order to deliver a positive message of support each of the black dogs had a “collar of hope” and all of them wore coats designed by celebrities, artists or members of the public.

Celebrity Support

SANE have a distinguished group of high-profile patrons. Over the years they have lent their time and energy to publicising services, backing campaigns and fundraising for continued growth and success of the charity.

Celebrity supporters include:

  • Ruby Wax.
  • Bradley Walsh.
  • Rory Bremner.
  • Ian Hislop.
  • James Arthur.
  • Joanna Lumley.
  • Michael Palin.
  • Trevor Phillips.
  • Adam Ant.

What is Rethink Mental Illness?

Introduction

Rethink Mental Illness is a mental health charity in England.

The organisation was founded in 1972 by John Pringle whose son was diagnosed with schizophrenia. The operating name of ‘Rethink’ was adopted in 2002, and expanded to ‘Rethink’ Mental Illness’ (to be more self-explanatory) in 2011, but the charity remains registered as the National Schizophrenia Fellowship, although it no longer focuses only on schizophrenia.

Rethink Mental Illness now has over 8,300 members, who receive a regular magazine called Your Voice. The charity states that it helps 48,000 people every year, and is for caregivers as well as those with a mental disorders. It provides services (mainly community support, including supported housing projects), support groups, and information through a helpline and publications. The Rethink Mental Illness website receives almost 300,000 visitors every year. Rethink Mental Illness carries out some survey research which informs both their own and national mental health policy, and it actively campaigns against stigma and for change through greater awareness and understanding. It is a member organisation of EUFAMI, the European Federation of Families of People with Mental Illness.

Brief History

John Pringle published an anonymous article in The Times on 09 May 1970, describing the ways that his son’s schizophrenia diagnosis had affected his family, and what his experience caring for his son was like. This article and the support it gathered was the starting point for the National Schizophrenia Fellowship, which was founded by Pringle in 1972.

In its early days, the National Schizophrenia Fellowship acted as a support group and charity for individuals caring for loved ones diagnosed with schizophrenia. The organisation was more robust than previous charities and support organisations, because of its emphasis on helping its constituents understand more about mental health, seek out community for people affected by schizophrenia, and look after their own mental health while caring for loved ones affected by mental illness.

The National Schizophrenia Fellowship was instrumental in promoting the new early psychosis paradigm in 1995 when they linked with an early psychosis network in the West Midlands, called IRIS (Initiative to reduce impact of schizophrenia). This then led to the Early Psychosis Declaration by the World Health Organisation (WHO) and the subsequent formation of early psychosis services as part of mainstream health policy.

In 2002, the organisation rebranded itself as Rethink to reflect its expanded focus on mental health, before later rebranding to Rethink Mental Illness in 2011.

Rethink commissioned a controversial statue of Sir Winston Churchill in a straitjacket, which was unveiled in The Forum building in Norwich on 11 March 2006, to a mixture of praise and criticism. This was part of Rethink’s first anti-stigma regional campaign. The statue was intended to show how people in today’s society are stigmatised by mental illness, based on claims that Churchill suffered from depression and perhaps bipolar disorder. However, the statue was condemned by Churchill’s family, and described by Sir Patrick Cormack as an insult both to the former prime minister and to people with mental health problems. Although straitjackets have not been used in UK psychiatric hospitals for decades, a sufferer from bipolar disorder identified with “the straitjacket of mental illness” and commended the image. Nevertheless, in response to the complaints, the statue was removed.

Mark Winstanley succeeded Paul Jenkins as chief executive officer of Rethink Mental Illness in March 2014.

Campaigns

Amongst its recent campaigns Rethink has urged the government to look at the mental health risks of cannabis, rather than “fiddle with its legal status”. Cannabis was downgraded from a Class B to a Class C drug in 2004, making most cases of possession non-arrestable. However, Rethink wants government support for new research into the relationship between severe mental illness and cannabis. They have publicly stated, in response to George Michael’s advocacy of the drug, that cannabis is the drug “most likely to cause mental illness”.

In 2009, Rethink launched Time to Change, a campaign to reduce mental health discrimination in England, in collaboration with MIND. and aims to empower people to challenge stigma and speak openly about their own mental health experiences, as well as changing the attitudes and behaviour of the public towards those of us with mental health problems.

In January 2014, Rethink Mental Illness launched a campaign to “Find Mike”, a stranger who talked a 20-year-old man, Jonny Benjamin, out of taking his life in 2008. The campaign aimed to reunite the two men, with Benjamin seeking to “thank the man who saved my life” after talking him down from Waterloo Bridge, and raise awareness of mental health issues. The campaign spread quickly on social media, and within two days, the stranger’s fiancée spotted it on Facebook and knew instantly that “Mike” was her partner Neil Laybourn. The two arranged to meet, with the moment captured on Channel 4 documentary The Stranger on the Bridge, which explored the issues of the campaign. In March 2016, the Duke and Duchess of Cambridge hosted a screening of The Stranger on the Bridge at Kensington Palace, and a discussion alongside Jonny Benjamin.

Rethink Mental Illness, represented by their CEO Mark Winstanley, is a member of the independent Mental Health Taskforce. The Taskforce was responsible for developing a comprehensive five year strategy for mental health in England. It was the first time that a strategic approach has been taken to improving mental health outcomes across England’s health and social care system. NHS England welcomed the Taskforce’s recommendations, and pledged to invest more than a billion pounds a year by 2021. Health Secretary Jeremy Hunt commented on the report’s publication, saying: “We will work across Government and with the NHS to make the recommendations in this landmark report a reality, so that we truly deliver equality between mental and physical health.”

Rethink Mental Illness provides part of the secretariat for the All Party Parliamentary Group on Mental Health. They help shape the group’s agenda and organise meetings of MPs and Peers with an interest in mental health. This work has included leading enquiries on topics such as:

  • Reducing premature mortality for people with mental health problems.
  • Improving the quality of mental health emergency care.
  • Mental wellbeing as a public health priority.

Funding

Rethink Mental Illness has an annual income of approximately £32.7 million, according to its Directors, Trustees and Consolidated Financial Statements Report for the year ended 31 March 2019.

The vast majority of this income comes from contracts to provide a wide range of mental health services commissioned by statutory sources including local governmental health and social care bodies. Currently around £1.5 million of its income derives from individual donations, membership and corporate relationships.

Rethink Mental Illness says it protects its independent voice by making clear with funders that no donation can challenge its independence in any way, and its corporate partners sign up to a written agreement stating this position. The organisation accepts funding from pharmaceutical companies on the basis that, as with its other funders, these gifts can support its work without compromising it. It says that its discussions with pharmaceutical companies about medication and treatments will always be unrelated to any funds received from them, and that it does not endorse particular drugs or treatments. There are statements on its site about its recent funding from pharmaceutical companies – these contributions account for less than 0.1% of the charity’s overall funding.

What is Paliperidone?

Introduction

Paliperidone, sold under the trade name Invega among others, is an atypical antipsychotic. It is mainly used to treat schizophrenia and schizoaffective disorder.

It is marketed by Janssen Pharmaceuticals. An extended release formulation is available that uses the OROS extended release system to allow for once-daily dosing. Paliperidone palmitate is a long-acting injectable formulation of paliperidone palmitoyl ester.

It is on the World Health Organisation’s List of Essential Medicines.

Brief History

Paliperidone (as Invega) was approved by the US Food and Drug Administration (FDA) for the treatment of schizophrenia in 2006. Paliperidone was approved by the FDA for the treatment of schizoaffective disorder in 2009. The long-acting injectable form of paliperidone, marketed as Invega Sustenna in US and Xeplion in Europe, was approved by the FDA on 31 July 2009. It is the only available brand in Bangladesh under the brand name “Palimax ER” manufactured & marketed by ACI Pharmaceuticals.

It was initially approved in Europe in 2007 for schizophrenia, the extended release form and use for schizoaffective disorder were approved in Europe in 2010, and extension to use in adolescents older than 15 years old was approved in 2014.

Medical Uses

It is used for the treatment of schizophrenia and schizoaffective disorder.

Adverse Effects

  • Very Common (>10% incidence):
    • Headache.
    • Tachycardia.
    • Somnolence (causes less sedation than most atypical antipsychotics).
    • Insomnia.
    • Hyperprolactinaemia (seems to cause comparable prolactin elevation to its parent drug, risperidone).
    • Sexual Dysfunction.
  • Common (1-10% incidence):
    • Cough.
    • Extrapyramidal side effects (EPSE; e.g. dystonia, akathisia, muscle rigidity, parkinsonism. It appears to produce similar EPSE to risperidone, asenapine and ziprasidone and more EPSE than olanzapine, clozapine, aripiprazole, quetiapine, amisulpride and sertindole).
    • Orthostatic hypotension.
    • Weight gain (tends to produce a moderate degree of weight gain, possibly related to its potent blockade of the 5-HT2C receptor).
    • QT interval prolongation (tends to produce less QT interval prolongation than most other atypical antipsychotics and approximately as much QT interval prolongation as aripiprazole and lurasidone).
    • Nasopharyngitis.
    • Anxiety.
    • Indigestion.
    • Constipation.

Discontinuation

The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse. Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite. Other symptoms may include restlessness, increased sweating, and trouble sleeping. Less commonly there may be a feeling of the world spinning, numbness, or muscle pains. Symptoms generally resolve after a short period of time.

There is tentative evidence that discontinuation of antipsychotics can result in psychosis. It may also result in reoccurrence of the condition that is being treated. Rarely tardive dyskinesia can occur when the medication is stopped.

Deaths

In April 2014, it was reported that 21 Japanese people who had received shots of the long-acting injectable paliperidone to date had died, out of 10,700 individuals prescribed the drug.

Pharmacology

Paliperidone is the primary active metabolite of the older antipsychotic risperidone. While its specific mechanism of action is unknown, it is believed paliperidone and risperidone act via similar, if not identical, pathways. Its efficacy is believed to result from central dopaminergic and serotonergic antagonism. Food is known to increase the absorption of Invega type ER OROS prolonged-release tablets. Food increased exposure of paliperidone by up to 50-60%, however, half-life was not significantly affected. The effect was probably due to a delay in the transit of the ER OROS formulation in the upper part of the GI channel, resulting in increased absorption.

The half-life is 23 hours.

Risperidone and its metabolite paliperidone are reduced in efficacy by P-glycoprotein inducers such as St John’s wort.

Brand Names

On 18 May 2015, a new formulation of paliperidone palmitate was approved by the FDA under the brand name Invega Trinza. A similar 3 -monthly injection of prolonged release suspension was approved in 2016 by the European Medicines Agency originally under the brand name Paliperidone Janssen, later renamed to Trevicta. On 01 September 2021, a newer formulation of paliperidone palmitate, Invega Hafyera, was approved by the FDA which is available as an injection every six months.

What is Risperidone?

Introduction

Risperidone, sold under the brand name Risperdal among others, is an atypical antipsychotic used to treat schizophrenia and bipolar disorder.

It is taken either by mouth or by injection into a muscle. The injectable version is long-acting and lasts for about two weeks.

Common side effects include movement problems, sleepiness, dizziness, trouble seeing, constipation, and increased weight. Serious side effects may include the potentially permanent movement disorder tardive dyskinesia, as well as neuroleptic malignant syndrome, an increased risk of suicide, and high blood sugar levels. In older people with psychosis as a result of dementia, it may increase the risk of dying. It is unknown if it is safe for use in pregnancy. Its mechanism of action is not entirely clear, but is believed to be related to its action as a dopamine and serotonin antagonist.

Study of risperidone began in the late 1980s and it was approved for sale in the United States in 1993. It is on the World Health Organisation’s List of Essential Medicines. It is available as a generic medication. In 2018, it was the 159th most commonly prescribed medication in the United States, with more than 3 million prescriptions.

Medical Uses

Risperidone is mainly used for the treatment of schizophrenia, bipolar disorder, and irritability associated with autism.

Schizophrenia

Risperidone is effective in treating psychogenic polydipsia and the acute exacerbations of schizophrenia.

Studies evaluating the utility of risperidone by mouth for maintenance therapy have reached varying conclusions. A 2012 systematic review concluded that evidence is strong that risperidone is more effective than all first-generation antipsychotics other than haloperidol, but that evidence directly supporting its superiority to placebo is equivocal. A 2011 review concluded that risperidone is more effective in relapse prevention than other first- and second-generation antipsychotics with the exception of olanzapine and clozapine. A 2016 Cochrane review suggests that risperidone reduces the overall symptoms of schizophrenia, but firm conclusions are difficult to make due to very low-quality evidence. Data and information are scarce, poorly reported, and probably biased in favour of risperidone, with about half of the included trials developed by drug companies. The article raises concerns regarding the serious side effects of risperidone, such as parkinsonism.

Long-acting injectable formulations of antipsychotic drugs provide improved compliance with therapy and reduce relapse rates relative to oral formulations. The efficacy of risperidone long-acting injection appears to be similar to that of long acting injectable forms of first generation antipsychotics.

Bipolar Disorder

Second-generation antipsychotics, including risperidone, are effective in the treatment of manic symptoms in acute manic or mixed exacerbations of bipolar disorder. In children and adolescents, risperidone may be more effective than lithium or divalproex, but has more metabolic side effects. As maintenance therapy, long-acting injectable risperidone is effective for the prevention of manic episodes but not depressive episodes. The long-acting injectable form of risperidone may be advantageous over long acting first generation antipsychotics, as it is better tolerated (fewer extrapyramidal effects) and because long acting injectable formulations of first generation antipsychotics may increase the risk of depression.

Autism

Compared to placebo, risperidone treatment reduces certain problematic behaviours in autistic children, including aggression toward others, self-injury, challenging behaviour, and rapid mood changes. The evidence for its efficacy appears to be greater than that for alternative pharmacological treatments. Weight gain is an important adverse effect. Some authors recommend limiting the use of risperidone and aripiprazole to those with the most challenging behavioural disturbances in order to minimise the risk of drug-induced adverse effects. Evidence for the efficacy of risperidone in autistic adolescents and young adults is less persuasive.

Other Uses

Risperidone has shown promise in treating therapy-resistant obsessive-compulsive disorder, when serotonin reuptake inhibitors are not sufficient.

Risperidone has not demonstrated a benefit in the treatment of eating disorders or personality disorders.

While antipsychotic medications such as risperidone have a slight benefit in people with dementia, they have been linked to higher incidences of death and stroke. Because of this increased risk of death, treatment of dementia-related psychosis with risperidone is not US Drug and Food Administration (FDA) approved.

Forms

Available forms of risperidone include tablet, oral dissolving tablet, oral solution, and powder and solvent for suspension for injection.

Adverse Effects

Common side effects include movement problems, sleepiness, dizziness, trouble seeing, constipation, and increased weight. About 9 to 20% of people gained more than 7% of the baseline weight depending on the dose. Serious side effects may include the potentially permanent movement disorder tardive dyskinesia, as well as neuroleptic malignant syndrome, an increased risk of suicide, and high blood sugar levels. In older people with psychosis as a result of dementia, it may increase the risk of dying.

While atypical antipsychotics appear to have a lower rate of movement problems as compared to typical antipsychotics, risperidone has a high risk of movement problems among the atypicals. Atypical antipsychotics however are associated with a greater amount of weight gain.

Drug Interactions

  • Carbamazepine and other enzyme inducers may reduce plasma levels of risperidone.
    • If a person is taking both carbamazepine and risperidone, the dose of risperidone will likely need to be increased.
    • The new dose should not be more than twice the patient’s original dose.
  • CYP2D6 inhibitors, such as SSRI medications, may increase plasma levels of risperidone and those medications.
  • Since risperidone can cause hypotension, its use should be monitored closely when a patient is also taking antihypertensive medicines to avoid severe low blood pressure.
  • Risperidone and its metabolite paliperidone are reduced in efficacy by P-glycoprotein inducers such as St John’s wort.

Discontinuation

The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotic treatment to avoid acute withdrawal syndrome or rapid relapse. Some have argued the additional somatic and psychiatric symptoms associated with dopaminergic super-sensitivity, including dyskinesia and acute psychosis, are common features of withdrawal in individuals treated with neuroleptics. This has led some to suggest the withdrawal process might itself be schizomimetic, producing schizophrenia-like symptoms even in previously healthy patients, indicating a possible pharmacological origin of mental illness in a yet unknown percentage of patients currently and previously treated with antipsychotics. This question is unresolved, and remains a highly controversial issue among professionals in the medical and mental health communities, as well as the public.

Dementia

Older people with dementia-related psychosis are at a higher risk of death if they take risperidone compared to those who do not. Most deaths are related to heart problems or infections.

Pharmacology

Pharmacodynamics

Risperidone has been classified as a “qualitatively atypical” antipsychotic agent with a relatively low incidence of extrapyramidal side effects (when given at low doses) that has more pronounced serotonin antagonism than dopamine antagonism. Risperidone contains the functional groups of benzisoxazole and piperidine as part of its molecular structure. Although not a butyrophenone, it was developed with the structures of benperidol and ketanserin as a basis. It has actions at several 5-HT (serotonin) receptor subtypes. These are 5-HT2C, linked to weight gain, 5-HT2A, linked to its antipsychotic action and relief of some of the extrapyramidal side effects experienced with the typical neuroleptics.[46]

It was recently found that D-amino acid oxidase, the enzyme that catalyses the breakdown of D-amino acids (e.g. D-alanine and D-serine – the neurotransmitters) is inhibited by risperidone.

Risperidone acts on the following receptors:

ReceptorsDescription
DopamineThis drug is an antagonist of the D1 (D1, and D5) as well as the D2 family (D2, D3 and D4) receptors, with 70-fold selectivity for the D2 family. This drug has “tight binding” properties, which means it has a long half-life and like other antipsychotics, risperidone blocks the mesolimbic pathway, the prefrontal cortex limbic pathway, and the tuberoinfundibular pathway in the central nervous system. Risperidone may induce extrapyramidal side effects, akathisia and tremors, associated with diminished dopaminergic activity in the striatum. It can also cause sexual side effects, galactorrhoea, infertility, gynecomastia and, with chronic use reduced bone mineral density leading to breaks, all of which are associated with increased prolactin secretion.
SerotoninIts action at these receptors may be responsible for its lower extrapyramidal side effect liability (via the 5-HT2A/2C receptors) and improved negative symptom control compared to typical antipsychotics such as haloperidol for instance. Its antagonistic actions at the 5-HT2C receptor may account, in part, for its weight gain liability.
Alpha α1 AdrenergicThis action accounts for its orthostatic hypotensive effects and perhaps some of the sedating effects of risperidone.
Alpha α2 AdrenergicPerhaps greater positive, negative, affective and cognitive symptom control.
Histamine H1Effects on these receptors account for its sedation and reduction in vigilance. This may also lead to drowsiness and weight gain.
Voltage-Gated Sodium ChannelsBecause it accumulates in synaptic vesicles, Risperidone inhibits voltage-gated sodium channels at clinically used concentrations. Though this medication possesses similar effects to other typical and atypical antipsychotics, it does not possess an affinity for the muscarinic acetylcholine receptors. In many respects, this medication can be useful as an “acetylcholine release-promoter” similar to gastrointestinal drugs such as metoclopramide and cisapride.

Pharmacokinetics

Risperidone undergoes hepatic metabolism and renal excretion. Lower doses are recommended for patients with severe liver and kidney disease. The active metabolite of risperidone, paliperidone, is also used as an antipsychotic.

Society and Culture

Regulatory Status

Risperidone was approved by the FDA in 1993 for the treatment of schizophrenia. In 2003, the FDA approved risperidone for the short-term treatment of the mixed and manic states associated with bipolar disorder. In 2006, the FDA approved risperidone for the treatment of irritability in autistic children and adolescents. The FDA’s decision was based in part on a study of autistic people with severe and enduring problems of violent meltdowns, aggression, and self-injury; risperidone is not recommended for autistic people with mild aggression and explosive behaviour without an enduring pattern. On 22 August 2007, risperidone was approved as the only drug agent available for treatment of schizophrenia in youths, ages 13-17; it was also approved that same day for treatment of bipolar disorder in youths and children, ages 10-17, joining lithium.

Availability

Janssen’s patent on risperidone expired on 29 December 2003, opening the market for cheaper generic versions from other companies, and Janssen’s exclusive marketing rights expired on 29 June 2004 (the result of a paediatric extension). It is available under many brand names worldwide.

Risperidone is available as a tablet, an oral solution, and an ampule, which is a depot injection.

Lawsuits

On 11 April 2012, Johnson & Johnson (J&J) and its subsidiary Janssen Pharmaceuticals Inc. were fined $1.2 billion by Judge Timothy Davis Fox of the Sixth Division of the Sixth Judicial Circuit of the US state of Arkansas. The jury found the companies had downplayed multiple risks associated with risperidone (Risperdal). The verdict was later reversed by the Arkansas State Supreme court.

In August 2012, Johnson & Johnson agreed to pay $181 million to 36 US states in order to settle claims that it had promoted risperidone and paliperidone for off-label uses including for dementia, anger management, and anxiety.

In November 2013, J&J was fined $2.2 billion for illegally marketing risperidone for use in people with dementia.

In 2015, Steven Brill posted a 15-part investigative journalism piece on J&J in The Huffington Post, called “America’s most admired lawbreaker”, which was focused on J&J’s marketing of risperidone.

J&J has faced numerous civil lawsuits on behalf of children who were prescribed risperidone who grew breasts (a condition called gynecomastia); as of July 2016 there were about 1,500 cases in Pennsylvania state court in Philadelphia, and there had been a February 2015 verdict against J&J with $2.5 million awarded to a man from Alabama, a $1.75M verdict against J&J that November, and in 2016 a $70 million verdict against J&J. In October, 2019, a jury awarded a Pennsylvania man $8 billion in a verdict against J&J.

Names

Brand names include Risperdal, Risperdal Consta, Risperdal M-Tab, Risperdal Quicklets, and Risperlet.

What is Metacognitive Training?

Introduction

Metacognitive training, (MCT), is an approach for treating the symptoms of psychosis in schizophrenia, especially delusions, which has been adapted for other disorders such as depression, obsessive-compulsive disorder and borderline personality disorder over the years (see below and external links for free download).

It was developed by Steffen Moritz and Todd Woodward. The intervention is based on the theoretical principles of cognitive behavioural therapy (CBT), but focuses in particular on problematic thinking styles (cognitive biases) that are associated with the development and maintenance of positive symptoms, e.g. overconfidence in errors and jumping to conclusions. Metacognitive training exists as a group training (MCT) and as an individualized intervention (MCT+).

Refer to Metacognitive Therapy.

Background

Metacognition can be defined as “thinking about thinking”. Over the course of the training, cognitive biases subserving positive symptoms are identified and corrected. The current empirical evidence assumes a connection between certain cognitive biases, such as jumping to conclusions, and the development and maintenance of psychosis. Accordingly, correcting these problematic/unhelpful thinking styles should lead to a reduction of symptoms.

Intervention

In eight training units (modules) and two additional modules, examples of “cognitive traps”, which can promote the development and maintenance of the positive symptoms of schizophrenia, are presented to patients in a playful way. Patients are instructed to critically reflect on their thought patterns, which may contribute to problematic behaviours, and to implement the contents of the training in everyday life. MCT deals with the following problematic styles of thinking: monocausal attributions, jumping to conclusions, inflexibility, problems in social cognition, overconfidence for memory errors and depressive thought patterns. The additional modules deal with stigma and low self-esteem. Individualised metacognitive training (MCT+) targets the same symptoms and cognitive biases as the group training, but is more flexible in that it allows discussion of individualised topics. The treatment materials for the group training can be obtained free of charge in over 30 languages from the website.

Efficacy

A recent meta-analysis found significant improvements for positive symptoms and delusions, as well as the acceptance of the training. These findings have been replicated in 2018 and 2019. An older meta-analysis based on a smaller number of studies found a small effect, which reached significance when newer studies were considered. Individual studies provide evidence for the long-term effectiveness of the approach beyond the immediate treatment period. MCT is recommended as an evidence-based treatment by the Royal Australian and New Zealand College of Psychiatrists as well as the German Association for Psychiatry, Psychotherapy and Psychosomatics.

Adaptations to other Disorders

Since its introduction, MCT has been adapted to other mental disorders. Empirical studies have been carried out for borderline personality disorder, obsessive-compulsive disorder (self-help approach), depression, bipolar disorders, and problem gambling.

Links (External)

What is Carbamazepine?

Introduction

Carbamazepine (CBZ), sold under the trade name Tegretol among others, is an anticonvulsant medication used primarily in the treatment of epilepsy and neuropathic pain.

It is used as an adjunctive treatment in schizophrenia along with other medications and as a second-line agent in bipolar disorder. Carbamazepine appears to work as well as phenytoin and valproate for focal and generalised seizures. It is not effective for absence or myoclonic seizures.

Common side effects include nausea and drowsiness. Serious side effects may include skin rashes, decreased bone marrow function, suicidal thoughts, or confusion. It should not be used in those with a history of bone marrow problems. Use during pregnancy may cause harm to the baby; however, stopping the medication in pregnant women with seizures is not recommended. Its use during breastfeeding is not recommended. Care should be taken in those with either kidney or liver problems.

Carbamazepine was discovered in 1953 by Swiss chemist Walter Schindler. It was first marketed in 1962. It is available as a generic medication. It is on the World Health Organisation’s List of Essential Medicines. In 2018, it was the 204th most commonly prescribed medication in the United States, with more than 2 million prescriptions. The newer but structurally related drugs, Oxcarbazepine and eslicarbazepine acetate, both show similar interactions, adverse events, and mechanism of action profiles.

Brief History

Carbamazepine was discovered by chemist Walter Schindler at J.R. Geigy AG (now part of Novartis) in Basel, Switzerland, in 1953. It was first marketed as a drug to treat epilepsy in Switzerland in 1963 under the brand name “Tegretol”; its use for trigeminal neuralgia (formerly known as tic douloureux) was introduced at the same time. It has been used as an anticonvulsant and antiepileptic in the UK since 1965, and has been approved in the US since 1968.

In 1971, Drs. Takezaki and Hanaoka first used carbamazepine to control mania in patients refractory to antipsychotics (lithium was not available in Japan at that time). Dr. Okuma, working independently, did the same thing with success. As they were also epileptologists, they had some familiarity with the anti-aggression effects of this drug. Carbamazepine was studied for bipolar disorder throughout the 1970s.

Medical Uses

Carbamazepine is typically used for the treatment of seizure disorders and neuropathic pain. It is used off-label as a second-line treatment for bipolar disorder and in combination with an antipsychotic in some cases of schizophrenia when treatment with a conventional antipsychotic alone has failed. However, evidence does not support this usage. It is not effective for absence seizures or myoclonic seizures. Although carbamazepine may have a similar effectiveness (people continue on medication) and efficacy (medicine reduces seizure recurrence and improves remission) when compared to phenytoin and valproate the choice of medications should be considered for each person individually as further research is needed to determine which medication is most helpful for people with newly-onset seizures.

In the United States, the FDA-approved medical uses are epilepsy (including partial seizures, generalised tonic-clonic seizures and mixed seizures), trigeminal neuralgia, and manic and mixed episodes of bipolar I disorder.

The drug is also claimed to be effective for ADHD.

As of 2014, a controlled release formulation was available for which there is tentative evidence showing fewer side effects and unclear evidence with regard to whether there is a difference in efficacy.

Adverse Effects

In the US, the label for carbamazepine contains warnings concerning:

  • Effects on the body’s production of red blood cells, white blood cells, and platelets: rarely, there are major effects of aplastic anaemia and agranulocytosis reported and more commonly, there are minor changes such as decreased white blood cell or platelet counts, but these do not progress to more serious problems.
  • Increased risks of suicide.
  • Increased risks of hyponatremia and syndrome of inappropriate antidiuretic hormone secretion (SIADH).
  • Risk of seizures, if the person stops taking the drug abruptly.
  • Risks to the foetus in women who are pregnant, specifically congenital malformations like spina bifida, and developmental disorders.

Common adverse effects may include drowsiness, dizziness, headaches and migraines, motor coordination impairment, nausea, vomiting, and/or constipation. Alcohol use while taking carbamazepine may lead to enhanced depression of the central nervous system.[2] Less common side effects may include increased risk of seizures in people with mixed seizure disorders,[21] abnormal heart rhythms, blurry or double vision.[2] Also, rare case reports of an auditory side effect have been made, whereby patients perceive sounds about a semitone lower than previously; this unusual side effect is usually not noticed by most people, and disappears after the person stops taking carbamazepine.

Pharmacogenetics

Serious skin reactions such as Stevens–Johnson syndrome or toxic epidermal necrolysis due to carbamazepine therapy are more common in people with a particular human leukocyte antigen allele, HLA-B1502. Odds ratios for the development of Stevens-Johnson syndrome or toxic epidermal necrolysis (SJS/TEN) in people who carry the allele can be in the double, triple or even quadruple digits, depending on the population studied. HLA-B1502 occurs almost exclusively in people with ancestry across broad areas of Asia, but has a very low or absent frequency in European, Japanese, Korean and African populations. However, the HLA-A31:01 allele has been shown to be a strong predictor of both mild and severe adverse reactions, such as the DRESS form of severe cutaneous reactions, to carbamazepine among Japanese, Chinese, Korean, and Europeans. It is suggested that carbamazepine acts as a potent antigen that binds to the antigen-presenting area of HLA-B1502 alike, triggering an everlasting activation signal on immature CD8-T cells, thus resulting in widespread cytotoxic reactions like SJS/TEN.

Interactions

Carbamazepine has a potential for drug interactions. Drugs that decrease breaking down of carbamazepine or otherwise increase its levels include erythromycin, cimetidine, propoxyphene, and calcium channel blockers. Grapefruit juice raises the bioavailability of carbamazepine by inhibiting the enzyme CYP3A4 in the gut wall and in the liver. Lower levels of carbamazepine are seen when administrated with phenobarbital, phenytoin, or primidone, which can result in breakthrough seizure activity.

Valproic acid and valnoctamide both inhibit microsomal epoxide hydrolase (mEH), the enzyme responsible for the breakdown of the active metabolite carbamazepine-10,11-epoxide into inactive metabolites. By inhibiting mEH, valproic acid and valnoctamide cause a build-up of the active metabolite, prolonging the effects of carbamazepine and delaying its excretion.

Carbamazepine, as an inducer of cytochrome P450 enzymes, may increase clearance of many drugs, decreasing their concentration in the blood to subtherapeutic levels and reducing their desired effects. Drugs that are more rapidly metabolized with carbamazepine include warfarin, lamotrigine, phenytoin, theophylline, valproic acid, many benzodiazepines, and methadone. Carbamazepine also increases the metabolism of the hormones in birth control pills and can reduce their effectiveness, potentially leading to unexpected pregnancies.

Pharmacology

Mechanism of Action

Carbamazepine is a sodium channel blocker. It binds preferentially to voltage-gated sodium channels in their inactive conformation, which prevents repetitive and sustained firing of an action potential. Carbamazepine has effects on serotonin systems but the relevance to its anti-seizure effects is uncertain. There is evidence that it is a serotonin releasing agent and possibly even a serotonin reuptake inhibitor.

Pharmacokinetics

Carbamazepine is relatively slowly but practically completely absorbed after administration by mouth. Highest concentrations in the blood plasma are reached after 4 to 24 hours depending on the dosage form. Slow release tablets result in about 15% lower absorption and 25% lower peak plasma concentrations than ordinary tablets, as well as in less fluctuation of the concentration, but not in significantly lower minimum concentrations.

20 to 30% of the substance are circulating in form of carbamazepine itself, the rest are metabolites. 70 to 80% are bound to plasma proteins. Concentrations in the breast milk are 25 to 60% of those in the blood plasma.

Carbamazepine itself is not pharmacologically active. It is activated, mainly by CYP3A4, to carbamazepine-10,11-epoxide, which is solely responsible for the drug’s anticonvulsant effects. The epoxide is then inactivated by microsomal epoxide hydrolase (mEH) to carbamazepine-trans-10,11-diol and further to its glucuronides. Other metabolites include various hydroxyl derivatives and carbamazepine-N-glucuronide.

The plasma half-life is about 35 to 40 hours when carbamazepine is given as single dose, but it is a strong inducer of liver enzymes, and the plasma half-life shortens to about 12 to 17 hours when it is given repeatedly. The half-life can be further shortened to 9-10 hours by other enzyme inducers such as phenytoin or phenobarbital. About 70% are excreted via the urine, almost exclusively in form of its metabolites, and 30% via the faeces.

Society and Culture

Environmental Impact

Carbamazepine and its (bio-)transformation products have been detected in wastewater treatment plant effluent  and in streams receiving treated wastewater. Field and laboratory studies have been conducted to understand the accumulation of carbamazepine in food plants grown in soil treated with sludge, which vary with respect to the concentrations of carbamazepine present in sludge and in the concentrations of sludge in the soil. Taking into account only studies that used concentrations commonly found in the environment, a 2014 review concluded that “the accumulation of carbamazepine into plants grown in soil amended with biosolids poses a de minimis risk to human health according to the approach.” 

Brand Names

Carbamazepine is available worldwide under many brand names including Tegretol.