Tag: Schizophrenia

What is SANE (Charity)?

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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?

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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?

Published on by Andrew Marshall6 Comments

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?

Published on by Andrew Marshall21 Comments

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?

Published on by Andrew Marshall1 Comment

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?

Published on by Andrew Marshall26 Comments

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.

What is Olanzapine?

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Introduction

Olanzapine, sold under the trade name Zyprexa among others, is an atypical antipsychotic primarily used to treat schizophrenia and bipolar disorder.

For schizophrenia, it can be used for both new-onset disease and long-term maintenance. It is taken by mouth or by injection into a muscle.

Common side effects include weight gain, movement disorders, dizziness, feeling tired, constipation, and dry mouth. Other side effects include low blood pressure with standing, allergic reactions, neuroleptic malignant syndrome, high blood sugar, seizures, gynecomastia, erectile dysfunction, and tardive dyskinesia. In older people with dementia, its use increases the risk of death. Use in the later part of pregnancy may result in a movement disorder in the baby for some time after birth. Although how it works is not entirely clear, it blocks dopamine and serotonin receptors.

Brief History

Olanzapine was patented in 1971 and approved for medical use in the United States in 1996. It is available as a generic medication. In 2017, it was the 239th-most commonly prescribed medication in the United States, with more than two million prescriptions. Lilly also markets olanzapine in a fixed-dose combination with fluoxetine as olanzapine/fluoxetine (Symbyax).

Chemical Synthesis

The preparation of olanzapine was first disclosed in a series of patents from Eli Lilly & Co. in the 1990s. In the final two steps, 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile was reduced with stannous chloride in ethanol to give the substituted thienobenzodiazepine ring system, and this was treated with methylpiperazine in a mixture of dimethyl sulfoxide and toluene as solvent to produce the drug.

Medical Uses

Schizophrenia

The first-line psychiatric treatment for schizophrenia is antipsychotic medication, with olanzapine being one such medication. Olanzapine appears to be effective in reducing symptoms of schizophrenia, treating acute exacerbations, and treating early-onset schizophrenia. The usefulness of maintenance therapy, however, is difficult to determine, as more than half of people in trials quit before the 6-week completion date. Treatment with olanzapine (like clozapine) may result in increased weight gain and increased glucose and cholesterol levels when compared to most other second-generation antipsychotic drugs used to treat schizophrenia.

Comparison

The UK National Institute for Health and Care Excellence (NICE), the British Association for Psychopharmacology, and the World Federation of Societies for Biological Psychiatry suggest that little difference in effectiveness is seen between antipsychotics in prevention of relapse, and recommend that the specific choice of antipsychotic be chosen based on a person’s preference and the drug’s side-effect profile. The US Agency for Healthcare Research and Quality concludes that olanzapine is not different from haloperidol in the treatment of positive symptoms and general psychopathology, or in overall assessment, but that it is superior for the treatment of negative and depressive symptoms. It has a lower risk of causing movement disorders than typical antipsychotics.

In a 2013 comparison of fifteen antipsychotic drugs in schizophrenia, olanzapine was ranked third in efficacy. It was 5% more effective than risperidone (fourth), 24-27% more effective than haloperidol, quetiapine, and aripiprazole, and 33% less effective than clozapine (first). A 2013 review of first-episode schizophrenia concluded that olanzapine is superior to haloperidol in providing a lower discontinuation rate, and in short-term symptom reduction, response rate, negative symptoms, depression, cognitive function, discontinuation due to poor efficacy, and long-term relapse, but not in positive symptoms or on the clinical global impressions (CGI) score. In contrast, pooled second-generation antipsychotics showed superiority to first-generation antipsychotics only against the discontinuation, negative symptoms (with a much larger effect seen among industry- compared to government-sponsored studies), and cognition scores. Olanzapine caused less extrapyramidal side effects and less akathisia, but caused significantly more weight gain, serum cholesterol increase, and triglyceride increase than haloperidol.

A 2012 review concluded that among ten atypical antipsychotics, only clozapine, olanzapine, and risperidone were better than first-generation antipsychotics. A 2011 review concluded that neither first- nor second-generation antipsychotics produce clinically meaningful changes in CGI scores, but found that olanzapine and amisulpride produce larger effects on the PANSS and BPRS batteries than five other second-generation antipsychotics or pooled first-generation antipsychotics. A 2010 Cochrane systematic review found that olanzapine may have a slight advantage in effectiveness when compared to aripiprazole, quetiapine, risperidone, and ziprasidone. No differences in effectiveness were detected when comparing olanzapine to amisulpride and clozapine. A 2014 meta-analysis of nine published trials having minimum duration six months and median duration 52 weeks concluded that olanzapine, quetiapine, and risperidone had better effects on cognitive function than amisulpride and haloperidol.

Bipolar Disorder

Olanzapine is recommended by NICE as a first-line therapy for the treatment of acute mania in bipolar disorder. Other recommended first-line treatments are haloperidol, quetiapine, and risperidone. It is recommended in combination with fluoxetine as a first-line therapy for acute bipolar depression, and as a second-line treatment by itself for the maintenance treatment of bipolar disorder.

The Network for Mood and Anxiety Treatments recommends olanzapine as a first-line maintenance treatment in bipolar disorder and the combination of olanzapine with fluoxetine as second-line treatment for bipolar depression.

A review on the efficacy of olanzapine as maintenance therapy in patients with bipolar disorder was published by Dando & Tohen in 2006. A 2014 meta-analysis concluded that olanzapine with fluoxetine was the most effective among nine treatments for bipolar depression included in the analysis.

Other Uses

Olanzapine may be useful in promoting weight gain in underweight adult outpatients with anorexia nervosa. However, no improvement of psychological symptoms was noted.

Olanzapine has been shown to be helpful in addressing a range of anxiety and depressive symptoms in individuals with schizophrenia and schizoaffective disorders, and has since been used in the treatment of a range of mood and anxiety disorders. Olanzapine is no less effective than lithium or valproate and more effective than placebo in treating bipolar disorder. It has also been used for Tourette syndrome and stuttering.

Olanzapine has been studied for the treatment of hyperactivity, aggressive behaviour, and repetitive behaviours in autism.

Olanzapine is frequently prescribed off-label for the treatment of insomnia, including difficulty falling asleep and staying asleep. The daytime sedation experienced with olanzapine is generally comparable to quetiapine and lurasidone, which is a frequent complaint in clinical trials. In some cases, the sedation due to olanzapine impaired the ability of people to wake up at a consistent time every day. Some evidence of efficacy for treating insomnia is seen, but long-term studies (especially for safety) are still needed.

Olanzapine has been recommended to be used in antiemetic regimens in people receiving chemotherapy that has a high risk for vomiting.

Specific Populations

Pregnancy and Lactation

Olanzapine is associated with the highest placental exposure of any atypical antipsychotic. Despite this, the available evidence suggests it is safe during pregnancy, although the evidence is insufficiently strong to say anything with a high degree of confidence. Olanzapine is associated with weight gain, which according to recent studies, may put olanzapine-treated patients’ offspring at a heightened risk for neural tube defects (e.g. spina bifida). Breastfeeding in women taking olanzapine is advised against because olanzapine is secreted in breast milk, with one study finding that the exposure to the infant is about 1.8% that of the mother.

Elderly

Citing an increased risk of stroke, in 2004, the Committee on the Safety of Medicines in the UK issued a warning that olanzapine and risperidone, both atypical antipsychotic medications, should not be given to elderly patients with dementia. In the US, olanzapine comes with a black box warning for increased risk of death in elderly patients. It is not approved for use in patients with dementia-related psychosis. A BBC investigation in June 2008 found that this advice was being widely ignored by British doctors. Evidence suggested that the elderly are more likely to experience weight gain on olanzapine compared to aripiprazole and risperidone.

Adverse Effects

Refer to Adverse Effects of Olanzapine.

The principal side effect of olanzapine is weight gain, which may be profound in some cases and/or associated with derangement in blood-lipid and blood-sugar profiles (see section metabolic effects). A 2013 meta-analysis of the efficacy and tolerance of 15 antipsychotic drugs (APDs) found that it had the highest propensity for causing weight gain out of the 15 APDs compared with an SMD of 0.74. Extrapyramidal side effects, although potentially serious, are infrequent to rare from olanzapine, but may include tremors and muscle rigidity.

It is not recommended to be used by IM injection in acute myocardial infarction, bradycardia, recent heart surgery, severe hypotension, sick sinus syndrome, and unstable angina.

Several patient groups are at a heightened risk of side effects from olanzapine and antipsychotics in general. Olanzapine may produce nontrivial high blood sugar in people with diabetes mellitus. Likewise, the elderly are at a greater risk of falls and accidental injury. Young males appear to be at heightened risk of dystonic reactions, although these are relatively rare with olanzapine. Most antipsychotics, including olanzapine, may disrupt the body’s natural thermoregulatory systems, thus permitting excursions to dangerous levels when situations (exposure to heat, strenuous exercise) occur.

Other side effects include galactorrhoea, amenorrhea, gynecomastia, and erectile dysfunction (impotence).

Paradoxical Effects

Olanzapine is used therapeutically to treat serious mental illness. Occasionally, it can have the opposite effect and provoke serious paradoxical reactions in a small subgroup of people, causing unusual changes in personality, thoughts, or behaviour; hallucinations and excessive thoughts about suicide have also been linked to olanzapine use.

Drug-Induced OCD

Many different types of medication can create or induce pure obsessive-compulsive disorder (OCD) in patients who have never had symptoms before. A new chapter about OCD in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (2013) now specifically includes drug-induced OCD.

Atypical antipsychotics (second-generation antipsychotics), such as olanzapine (Zyprexa), have been proven to induce de novo OCD in patients.

Metabolic Effects

The US Food and Drug Administration (FDA) requires all atypical antipsychotics to include a warning about the risk of developing hyperglycaemia and diabetes, both of which are factors in the metabolic syndrome. These effects may be related to the drugs’ ability to induce weight gain, although some reports have been made of metabolic changes in the absence of weight gain. Studies have indicated that olanzapine carries a greater risk of causing and exacerbating diabetes than another commonly prescribed atypical antipsychotic, risperidone. Of all the atypical antipsychotics, olanzapine is one of the most likely to induce weight gain based on various measures. The effect is dose dependent in humans and animal models of olanzapine-induced metabolic side effects. There are some case reports of olanzapine-induced diabetic ketoacidosis. Olanzapine may decrease insulin sensitivity, though one 3-week study seems to refute this. It may also increase triglyceride levels.

Despite weight gain, a large multicentre, randomised National Institute of Mental Health study found that olanzapine was better at controlling symptoms because patients were more likely to remain on olanzapine than the other drugs. One small, open-label, nonrandomised study suggests that taking olanzapine by orally dissolving tablets may induce less weight gain, but this has not been substantiated in a blinded experimental setting.

Post-Injection Delirium/Sedation Syndrome

Postinjection delirium/sedation syndrome (PDSS) is a rare syndrome that is specific to the long-acting injectable formulation of olanzapine, olanzapine pamoate. The incidence of PDSS with olanzapine pamoate is estimated to be 0.07% of administrations, and is unique among other second-generation, long-acting antipsychotics (e.g. paliperidone palmitate), which do not appear to carry the same risk.[70] PDSS is characterised by symptoms of delirium (e.g. confusion, difficulty speaking, and uncoordinated movements) and sedation. Most people with PDSS exhibit both delirium and sedation (83%). Although less specific to PDSS, a majority of cases (67%) involved a feeling of general discomfort. PDSS may occur due to accidental injection and absorption of olanzapine pamoate into the bloodstream, where it can act more rapidly, as opposed to slowly distributing out from muscle tissue. Using the proper, intramuscular-injection technique for olanzapine pamoate helps to decrease the risk of PDSS, though it does not eliminate it entirely. This is why the FDA advises that people who are injected with olanzapine pamoate be watched for 3 hours after administration, in the event that PDSS occurs.

Animal Toxicology

Olanzapine has demonstrated carcinogenic effects in multiple studies when exposed chronically to female mice and rats, but not male mice and rats. The tumours found were in either the liver or mammary glands of the animals.

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, vertigo, numbness, or muscle pains may occur. Symptoms generally resolve after a short time.

Tentative evidence indicates 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.

Overdose

Symptoms of an overdose include tachycardia, agitation, dysarthria, decreased consciousness, and coma. Death has been reported after an acute overdose of 450 mg, but also survival after an acute overdose of 2000 mg. Fatalities generally have occurred with olanzapine plasma concentrations greater than 1000 ng/mL post mortem, with concentrations up to 5200 ng/mL recorded (though this might represent confounding by dead tissue, which may release olanzapine into the blood upon death). No specific antidote for olanzapine overdose is known, and even physicians are recommended to call a certified poison control centre for information on the treatment of such a case. Olanzapine is considered moderately toxic in overdose, more toxic than quetiapine, aripiprazole, and the SSRIs, and less toxic than the monoamine oxidase inhibitors and tricyclic antidepressants.

Interactions

Drugs or agents that increase the activity of the enzyme CYP1A2, notably tobacco smoke, may significantly increase hepatic first-pass clearance of olanzapine; conversely, drugs that inhibit CYP1A2 activity (examples: ciprofloxacin, fluvoxamine) may reduce olanzapine clearance. Carbamazepine, a known enzyme inducer, has decreased the concentration/dose ration of olanzapine by 33% compared to olanzapine alone. Another enzyme inducer, ritonavir, has also been shown to decrease the body’s exposure to olanzapine, due to its induction of the enzymes CYP1A2 and uridine 5′-diphospho-glucuronosyltransferase (UGT). Probenecid increases the total exposure (area under the curve) and maximum plasma concentration of olanzapine. Although olanzapine’s metabolism includes the minor metabolic pathway of CYP2D6, the presence of the CYP2D6 inhibitor fluoxetine does not have a clinically significant effect on olanzapine’s clearance.

Pharmacology

Pharmacodynamics

Olanzapine has a higher affinity for 5-HT2A serotonin receptors than D2 dopamine receptors, which is a common property of most atypical antipsychotics, aside from the benzamide antipsychotics such as amisulpride along with the nonbenzamides aripiprazole, brexpiprazole, blonanserin, cariprazine, melperone, and perospirone.

Olanzapine had the highest affinity of any second-generation antipsychotic towards the P-glycoprotein in one in vitro study. P-glycoprotein transports a myriad of drugs across a number of different biological membranes (found in numerous body systems) including the blood-brain barrier (a semipermeable membrane that filters the contents of blood prior to it reaching the brain); P-GP inhibition could mean that less brain exposure to olanzapine results from this interaction with the P-glycoprotein. A relatively large quantity of commonly encountered foods and medications inhibit P-GP, and pharmaceuticals fairly commonly are either substrates of P-GP, or inhibit its action; both substrates and inhibitors of P-GP effectively increase the permeability of the blood-brain barrier to P-GP substrates and subsequently increase the central activity of the substrate, while reducing the local effects on the GI tract. The mediation of olanzapine in the central nervous system by P-GP means that any other substance or drug that interacts with P-GP increases the risk for toxic accumulations of both olanzapine and the other drug.

Olanzapine is a potent antagonist of the muscarinic M3 receptor, which may underlie its diabetogenic side effects. Additionally, it also exhibits a relatively low affinity for serotonin 5-HT1, GABAA, beta-adrenergic receptors, and benzodiazepine binding sites.

The mode of action of olanzapine’s antipsychotic activity is unknown. It may involve antagonism of dopamine and serotonin receptors. Antagonism of dopamine receptors is associated with extrapyramidal effects such as tardive dyskinesia (TD), and with therapeutic effects. Antagonism of muscarinic acetylcholine receptors is associated with anticholinergic side effects such as dry mouth and constipation; in addition, it may suppress or reduce the emergence of extrapyramidal effects for the duration of treatment, but it offers no protection against the development of TD. In common with other second-generation (atypical) antipsychotics, olanzapine poses a relatively low risk of extrapyramidal side effects including TD, due to its higher affinity for the 5HT2A receptor over the D2 receptor.

Antagonizing H1 histamine receptors causes sedation and may cause weight gain, although antagonistic actions at serotonin 5-HT2C and dopamine D2 receptors have also been associated with weight gain and appetite stimulation.

Pharmacokinetics

Metabolism

Olanzapine is metabolized by the cytochrome P450 (CYP) system; principally by isozyme 1A2 (CYP1A2) and to a lesser extent by CYP2D6. By these mechanisms, more than 40% of the oral dose, on average, is removed by the hepatic first-pass effect. Clearance of olanzapine appears to vary by sex; women have roughly 25% lower clearance than men. Clearance of olanzapine also varies by race; in self-identified African Americans or Blacks, olanzapine’s clearance was 26% higher. A difference in the clearance does not apparent between individuals identifying as Caucasian, Chinese, or Japanese. Routine, pharmacokinetic monitoring of olanzapine plasma levels is generally unwarranted, though unusual circumstances (e.g. the presence of drug-drug interactions) or a desire to determine if patients are taking their medicine may prompt its use.

Chemistry

Olanzapine is unusual in having four well-characterised crystalline polymorphs and many hydrated forms.

Society and Culture

Regulatory Status

Olanzapine is approved by the US FDA for:

  • Treatment – in combination with fluoxetine – of depressive episodes associated with bipolar disorder (December 2003).
  • Long-term treatment of bipolar I disorder (January 2004).
  • Long-term treatment – in combination with fluoxetine – of resistant depression (March 2009).
  • Oral formulation: acute and maintenance treatment of schizophrenia in adults, acute treatment of manic or mixed episodes associated with bipolar I disorder (monotherapy and in combination with lithium or sodium valproate).
  • Intramuscular formulation: acute agitation associated with schizophrenia and bipolar I mania in adults.
  • Oral formulation combined with fluoxetine: treatment of acute depressive episodes associated with bipolar I disorder in adults, or treatment of acute, resistant depression in adults.
  • Treatment of the manifestations of psychotic disorders (September 1996 to March 2000).
  • Short-term treatment of acute manic episodes associated with bipolar I disorder (March 2000).
  • Short-term treatment of schizophrenia instead of the management of the manifestations of psychotic disorders (March 2000).
  • Maintaining treatment response in schizophrenic patients who had been stable for about eight weeks and were then followed for a period of up to eight months (November 2000).

The drug became generic in 2011.

Sales of Zyprexa in 2008 were $2.2 billion in the US and $4.7 billion worldwide.

Controversy and Litigation

Eli Lilly has faced many lawsuits from people who claimed they developed diabetes or other diseases after taking Zyprexa, as well as by various governmental entities, insurance companies, and others. Lilly produced a large number of documents as part of the discovery phase of this litigation, which started in 2004; the documents were ruled to be confidential by a judge and placed under seal, and later themselves became the subject of litigation.

In 2006, Lilly paid $700 million to settle around 8,000 of these lawsuits, and in early 2007, Lilly settled around 18,000 suits for $500 million, which brought the total Lilly had paid to settle suits related to the drug to $1.2 billion.

A December 2006 New York Times article based on leaked company documents concluded that the company had engaged in a deliberate effort to downplay olanzapine’s side effects. The company denied these allegations and stated that the article had been based on cherry-picked documents. The documents were provided to the Times by Jim Gottstein, a lawyer who represented mentally ill patients, who obtained them from a doctor, David Egilman, who was serving as an expert consultant on the case. After the documents were leaked to online peer-to-peer, file-sharing networks by Will Hall and others in the psychiatric survivors movement, who obtained copies, in 2007 Lilly filed a protection order to stop the dissemination of some of the documents, which Judge Jack B. Weinstein of the Brooklyn Federal District Court granted. Judge Weinstein also criticized the New York Times reporter, Gottstein, and Egilman in the ruling. The Times of London also received the documents and reported that as early as 1998, Lilly considered the risk of drug-induced obesity to be a “top threat” to Zyprexa sales. On 09 October 2000, senior Lilly research physician Robert Baker noted that an academic advisory board to which he belonged was “quite impressed by the magnitude of weight gain on olanzapine and implications for glucose.”

Lilly had threatened Egilman with criminal contempt charges regarding the documents he took and provided to reporters; in September 2007, he agreed to pay Lilly $100,000 in return for the company’s agreement to drop the threat of charges.

In September 2008, Judge Weinstein issued an order to make public Lilly’s internal documents about the drug in a different suit brought by insurance companies, pension funds, and other payors.

In March 2008, Lilly settled a suit with the state of Alaska, and in October 2008, Lilly agreed to pay $62 million to 32 states and the District of Columbia to settle suits brought under state consumer protection laws.

In 2009, Eli Lilly pleaded guilty to a US federal criminal misdemeanour charge of illegally marketing Zyprexa for off-label use and agreed to pay $1.4 billion. The settlement announcement stated “Eli Lilly admits that between September 1999 and 31 March 2001, the company promoted Zyprexa in elderly populations as treatment for dementia, including Alzheimer’s dementia. Eli Lilly has agreed to pay a $515 million criminal fine and to forfeit an additional $100 million in assets.”

Trade Names

Olanzapine is generic and available under many trade names worldwide.

Dosage Forms

Olanzapine is marketed in a number of countries, with tablets ranging from 2.5 to 20 mg. Zyprexa (and generic olanzapine) is available as an orally disintegrating “wafer”, which rapidly dissolves in saliva. It is also available in 10-mg vials for intramuscular injection.

Research

Olanzapine has been studied as an antiemetic, particularly for the control of chemotherapy-induced nausea and vomiting (CINV).

In general, olanzapine appears to be about as effective as aprepitant for the prevention of CINV, though some concerns remain for its use in this population. For example, concomitant use of metoclopramide or haloperidol increases the risk for extrapyramidal symptoms. Otherwise, olanzapine appears to be fairly well tolerated for this indication, with somnolence being the most common side effect.

Olanzapine has been considered as part of an early psychosis approach for schizophrenia. The Prevention through Risk Identification, Management, and Education study, funded by the National Institute of Mental Health and Eli Lilly, tested the hypothesis that olanzapine might prevent the onset of psychosis in people at very high risk for schizophrenia. The study examined 60 patients with prodromal schizophrenia, who were at an estimated risk of 36-54% of developing schizophrenia within a year, and treated half with olanzapine and half with placebo. In this study, patients receiving olanzapine did not have a significantly lower risk of progressing to psychosis. Olanzapine was effective for treating the prodromal symptoms, but was associated with significant weight gain.

What is Imidazenil?

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Introduction

Imidazenil is an experimental anxiolytic drug which is derived from the benzodiazepine family, and is most closely related to other imidazobenzodiazepines such as midazolam, flumazenil, and bretazenil.

Outline

Imidazenil is a highly potent benzodiazepine receptor partial agonist with an unusual profile of effects, producing some of the effects associated with normal benzodiazepines such as anticonvulsant and anxiolytic effects, yet without any notable sedative or amnestic effects. In fact, imidazenil blocks the sedative effects of diazepam, yet without lowering the convulsion threshold, and so potentially could be a more flexible antidote than the antagonist flumazenil which is commonly used to treat benzodiazepine overdose at present.

As of August 2021, Imidazenil has not yet been developed commercially for use in humans, however it has been suggested as a safe and effective treatment for anxiety, a potent yet non-sedating anticonvulsant which might be particularly useful in the treatment of poisoning with organophosphate nerve agents, and as a novel treatment for schizophrenia.

What is Loxapine?

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Introduction

Loxapine, sold under the brand names Loxitane and Adasuve (inhalation only) among others, is a typical antipsychotic medication used primarily in the treatment of schizophrenia.

The drug is a member of the dibenzoxazepine class and structurally related to clozapine. Several researchers have argued that loxapine may behave as an atypical antipsychotic.

Loxapine may be metabolised by N-demethylation to amoxapine, a tricyclic antidepressant.

Medical Uses

The US Food and Drug Administration (FDA) has approved loxapine inhalation powder for the acute treatment of agitation associated with schizophrenia or bipolar I disorder in adults.

A brief review of loxapine found no conclusive evidence that it was particularly effective in patients with paranoid schizophrenia. A subsequent systematic review considered that the limited evidence did not indicate a clear difference in its effects from other antipsychotics.

Available Forms

Loxapine can be taken by mouth as a capsule or a liquid oral concentrate. It is also available as an intramuscular injection and as a powder for inhalation.

Side Effects

Loxapine can cause side effects that are generally similar to that of other medications in the typical antipsychotic class of medications. These include, e.g. gastrointestinal problems (like constipation and abdominal pain), cardiovascular problems (like tachycardia), moderate likelihood of drowsiness (relative to other antipsychotics), and movement problems (i.e. extrapyramidal symptoms (EPS)). At lower dosages its propensity for causing EPS appears to be similar to that of atypical antipsychotics. Although it is structurally similar to clozapine, it does not have the same risk of agranulocytosis (which, even with clozapine, is less than 1%); however, mild and temporary fluctuations in blood leukocyte levels can occur. Abuse of loxapine has been reported.

The inhaled formulation of loxapine carries a low risk for a type of airway adverse reaction called bronchospasm that is not thought to occur when loxapine is taken by mouth.

Pharmacology

Mechanism of Action

Loxapine is a “mid-potency” typical antipsychotic. However, unlike most other typical antipsychotics, it has significant potency at the 5HT2A receptor (6.6 nM), which is similar to atypical antipsychotics like clozapine (5.35 nM). The higher likelihood of EPS with loxapine, compared to clozapine, may be due to its high potency for the D2 receptor.

Pharmacokinetics

Loxapine is metabolised to amoxapine, as well as its 8-hydroxy metabolite (8-hydroxyloxapine). Amoxapine is further metabolized to its 8-hydroxy metabolite (8-hydroxyamoxapine), which is also found in the blood of people taking loxapine. At steady-state after taking loxapine by mouth, the relative amounts of loxapine and its metabolites in the blood is as follows: 8-hydroxyloxapine > 8-hydroxyamoxapine > loxapine.

The pharmacokinetics of loxapine change depending on how it is given. Intramuscular injections of loxapine lead to higher blood levels and area under the curve of loxapine than when it is taken by mouth.

Chemistry

Loxapine is a dibenzoxazepine and is structurally related to clozapine.

What is Haloperidol?

Published on by Andrew Marshall30 Comments

Introduction

Haloperidol, sold under the brand name Haldol among others, is a typical antipsychotic medication.

Haloperidol is used in the treatment of schizophrenia, tics in Tourette syndrome, mania in bipolar disorder, delirium, agitation, acute psychosis, and hallucinations in alcohol withdrawal. It may be used by mouth or injection into a muscle or a vein. Haloperidol typically works within 30 to 60 minutes. A long-acting formulation may be used as an injection every four weeks in people with schizophrenia or related illnesses, who either forget or refuse to take the medication by mouth.

Haloperidol may result in a movement disorder known as tardive dyskinesia which may be permanent. Neuroleptic malignant syndrome and QT interval prolongation may occur. In older people with psychosis due to dementia it results in an increased risk of death. When taken during pregnancy it may result in problems in the infant. It should not be used in people with Parkinson’s disease.

Haloperidol was discovered in 1958 by Paul Janssen. It was made from pethidine (meperidine). It is on the World Health Organisation’s (WHO’s) List of Essential Medicines. It is the most commonly used typical antipsychotic. In 2017, it was the 296th most commonly prescribed medication in the United States, with more than one million prescriptions.

Refer to Haloperidol Decanoate.

Brief History

Haloperidol was discovered by Paul Janssen. It was developed in 1958 at the Belgian company Janssen Pharmaceutica and submitted to the first of clinical trials in Belgium later that year.

Haloperidol was approved by the US Food and Drug Administration (FDA) on 12 April 1967; it was later marketed in the US and other countries under the brand name Haldol by McNeil Laboratories.

Medical Uses

Haloperidol is used in the control of the symptoms of:

  • Acute psychosis, such as drug-induced psychosis caused by LSD, psilocybin, amphetamines, ketamine, and phencyclidine, and psychosis associated with high fever or metabolic disease.
    • Some evidence, however, has found haloperidol to worsen psychosis due to psilocybin.
  • Adjunctive treatment of alcohol and opioid withdrawal.
  • Agitation and confusion associated with cerebral sclerosis.
  • Alcohol-induced psychosis.
  • Hallucinations in alcohol withdrawal.
  • Hyperactive delirium (to control the agitation component of delirium).
  • Hyperactivity, aggression.
  • Otherwise uncontrollable, severe behavioral disorders in children and adolescents.
  • Schizophrenia.
  • Therapeutic trial in personality disorders, such as borderline personality disorder.
  • Treatment of intractable hiccups.
  • Treatment of neurological disorders, such as tic disorders such as Tourette syndrome, and chorea.
  • Treatment of severe nausea and emesis in postoperative and palliative care, especially for palliating adverse effects of radiation therapy and chemotherapy in oncology.

Haloperidol was considered indispensable for treating psychiatric emergency situations, although the newer atypical drugs have gained a greater role in a number of situations as outlined in a series of consensus reviews published between 2001 and 2005.

In a 2013 comparison of 15 antipsychotics in schizophrenia, haloperidol demonstrated standard effectiveness. It was 13-16% more effective than ziprasidone, chlorpromazine, and asenapine, approximately as effective as quetiapine and aripiprazole, and 10% less effective than paliperidone.

Pregnancy and Lactation

Data from animal experiments indicate haloperidol is not teratogenic, but is embryotoxic in high doses. In humans, no controlled studies exist. Reports in pregnant women revealed possible damage to the foetus, although most of the women were exposed to multiple drugs during pregnancy. In addition, reports indicate neonates exposed to antipsychotic drugs are at risk for extrapyramidal and/or withdrawal symptoms following delivery, such as agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder. Following accepted general principles, haloperidol should be given during pregnancy only if the benefit to the mother clearly outweighs the potential foetal risk.

Haloperidol is excreted in breast milk. A few studies have examined the impact of haloperidol exposure on breastfed infants and in most cases, there were no adverse effects on infant growth and development.

Other Considerations

During long-term treatment of chronic psychiatric disorders, the daily dose should be reduced to the lowest level needed for maintenance of remission. Sometimes, it may be indicated to terminate haloperidol treatment gradually. In addition, during long-term use, routine monitoring including measurement of BMI, blood pressure, fasting blood sugar, and lipids, is recommended due to the risk of side effects.

Other forms of therapy (psychotherapy, occupational therapy/ergotherapy, or social rehabilitation) should be instituted properly. PET imaging studies have suggested low doses are preferable. Clinical response was associated with at least 65% occupancy of D2 receptors, while greater than 72% was likely to cause hyperprolactinaemia and over 78% associated with extrapyramidal side effects. Doses of haloperidol greater than 5 mg increased the risk of side effects without improving efficacy. Patients responded with doses under even 2 mg in first-episode psychosis. For maintenance treatment of schizophrenia, an international consensus conference recommended a reduction dosage by about 20% every 6 months until a minimal maintenance dose is established.

Depot forms are also available; these are injected deeply intramuscularly at regular intervals. The depot forms are not suitable for initial treatment, but are suitable for patients who have demonstrated inconsistency with oral dosages.

The decanoate ester of haloperidol (haloperidol decanoate, trade names Haldol decanoate, Halomonth, Neoperidole) has a much longer duration of action, so is often used in people known to be noncompliant with oral medication. A dose is given by intramuscular injection once every two to four weeks. The IUPAC name of haloperidol decanoate is [4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl] decanoate.

Topical formulations of haloperidol should not be used as treatment for nausea because research does not indicate this therapy is more effective than alternatives.

Adverse Effects

As haloperidol is a high-potency typical antipsychotic, it tends to produce significant extrapyramidal side effects. According to a 2013 meta-analysis of the comparative efficacy and tolerability of 15 antipsychotic drugs it was the most prone of the 15 for causing extrapyramidal side effects.

With more than 6 months of use 14 percent of users gain weight. Haloperidol may be neurotoxic.

  • Common (>1% incidence):
    • Extrapyramidal side effects including:
      • Akathisia (motor restlessness).
      • Dystonia (continuous spasms and muscle contractions).
      • Muscle rigidity.
      • Parkinsonism (characteristic symptoms such as rigidity).
    • Hypotension:
    • Anticholinergic side effects such as (These adverse effects are less common than with lower-potency typical antipsychotics, such as chlorpromazine and thioridazine):
      • Blurred vision.
      • Constipation.
      • Dry mouth.
    • Somnolence (which is not a particularly prominent side effect, as is supported by the results of the aforementioned meta-analysis).
  • Unknown frequency:
    • Anaemia.
    • Headache.
    • Increased respiratory rate.
    • Orthostatic hypotension.
    • Prolonged QT interval.
    • Visual disturbances.
  • Rare (<1% incidence):
    • Acute hepatic failure.
    • Agitation.
    • Agranulocytosis.
    • Anaphylactic reaction.
    • Anorexia.
    • Bronchospasm.
    • Cataracts.
    • Cholestasis.
    • Confusional state.
    • Depression.
    • Dermatitis exfoliative.
    • Dyspnoea.
    • Oedema.
    • Extrasystoles.
    • Face oedema.
    • Gynecomastia.
    • Hepatitis.
    • Hyperglycaemia.
    • Hypersensitivity.
    • Hyperthermia.
    • Hypoglycaemia.
    • Hyponatremia.
    • Hypothermia.
    • Increased sweating.
    • Injection site abscess.
    • Insomnia.
    • Itchiness.
    • Jaundice.
    • Laryngeal oedema.
    • Laryngospasm.
    • Leukocytoclastic vasculitis.
    • Leukopenia.
    • Liver function test abnormal.
    • Nausea.
    • Neuroleptic malignant syndrome.
    • Neutropenia.
    • Pancytopenia.
    • Photosensitivity reaction.
    • Priapism.
    • Psychotic disorder.
    • Pulmonary embolism.
    • Rash.
    • Retinopathy.
    • Seizure.
    • Sudden death.
    • Tardive dyskinesia.
    • Thrombocytopenia.
    • Torsades de pointes.
    • Urinary retention.
    • Urticaria.
    • Ventricular fibrillation.
    • Ventricular tachycardia.
    • Vomiting.

Contraindications

  • Pre-existing coma, acute stroke.
  • Severe intoxication with alcohol or other central depressant drugs.
  • Known allergy against haloperidol or other butyrophenones or other drug ingredients.
  • Known heart disease, when combined will tend towards cardiac arrest.

Special Cautions

  • A multiple-year study suggested this drug and other neuroleptic antipsychotic drugs commonly given to people with Alzheimer’s with mild behavioural problems often make their condition worse and its withdrawal was even beneficial for some cognitive and functional measures.
  • Elderly patients with dementia-related psychosis: analysis of 17 trials showed the risk of death in this group of patients was 1.6 to 1.7 times that of placebo-treated patients.
    • Most of the causes of death were either cardiovascular or infectious in nature.
    • It is not clear to what extent this observation is attributed to antipsychotic drugs rather than the characteristics of the patients.
    • The drug bears a boxed warning about this risk.
  • Impaired liver function, as haloperidol is metabolised and eliminated mainly by the liver.
  • In patients with hyperthyroidism, the action of haloperidol is intensified and side effects are more likely.
  • IV injections: risk of hypotension or orthostatic collapse.
  • Patients at special risk for the development of QT prolongation (hypokalaemia, concomitant use of other drugs causing QT prolongation).
  • Patients with a history of leukopenia: a complete blood count should be monitored frequently during the first few months of therapy and discontinuation of the drug should be considered at the first sign of a clinically significant decline in white blood cells.
  • Pre-existing Parkinson’s disease or dementia with Lewy bodies.

Interactions

  • Amiodarone: Q-Tc interval prolongation (potentially dangerous change in heart rhythm).
  • Amphetamine and methylphenidate: counteracts increased action of norepinephrine and dopamine in patients with narcolepsy or ADD/ADHD.
  • Epinephrine: action antagonised, paradoxical decrease in blood pressure may result.
  • Guanethidine: antihypertensive action antagonised.
  • Levodopa: decreased action of levodopa.
  • Lithium: rare cases of the following symptoms have been noted: encephalopathy, early and late extrapyramidal side effects, other neurologic symptoms, and coma.
  • Methyldopa: increased risk of extrapyramidal side effects and other unwanted central effects.
  • Other central depressants (alcohol, tranquilizers, narcotics): actions and side effects of these drugs (sedation, respiratory depression) are increased.
    • In particular, the doses of concomitantly used opioids for chronic pain can be reduced by 50%.
  • Other drugs metabolised by the CYP3A4 enzyme system: inducers such as carbamazepine, phenobarbital, and rifampicin decrease plasma levels and inhibitors such as quinidine, buspirone, and fluoxetine increase plasma levels.
  • Tricyclic antidepressants: metabolism and elimination of tricyclics significantly decreased, increased toxicity noted (anticholinergic and cardiovascular side effects, lowering of seizure threshold).

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.

Overdose

Symptoms

Symptoms are usually due to side effects. Most often encountered are:

  • Anticholinergic side effects (dry mouth, constipation, paralytic ileus, difficulties in urinating, decreased perspiration).
  • Coma in severe cases, accompanied by respiratory depression and massive hypotension, shock.
  • Hypotension or hypertension.
  • Rarely, serious ventricular arrhythmia (torsades de pointes), with or without prolonged QT-time.
  • Sedation.
  • Severe extrapyramidal side effects with muscle rigidity and tremors, akathisia, etc.

Treatment

Treatment is mostly symptomatic and involves intensive care with stabilisation of vital functions. In early detected cases of oral overdose, induction of emesis, gastric lavage, and the use of activated charcoal can be tried. In the case of a severe overdose, antidotes such as bromocriptine or ropinirole may be used to treat the extrapyramidal effects caused by haloperidol, acting as dopamine receptor agonists. ECG and vital signs should be monitored especially for QT prolongation and severe arrhythmias should be treated with antiarrhythmic measures.

Prognosis

In general, the prognosis of overdose is good, provided the person has survived the initial phase. An overdose of haloperidol can be fatal.

Pharmacology

Haloperidol is a typical butyrophenone type antipsychotic that exhibits high affinity dopamine D2 receptor antagonism and slow receptor dissociation kinetics. It has effects similar to the phenothiazines. The drug binds preferentially to D2 and α1 receptors at low dose (ED50 = 0.13 and 0.42 mg/kg, respectively), and 5-HT2 receptors at a higher dose (ED50 = 2.6 mg/kg). Given that antagonism of D2 receptors is more beneficial on the positive symptoms of schizophrenia and antagonism of 5-HT2 receptors on the negative symptoms, this characteristic underlies haloperidol’s greater effect on delusions, hallucinations and other manifestations of psychosis. Haloperidol’s negligible affinity for histamine H1 receptors and muscarinic M1 acetylcholine receptors yields an antipsychotic with a lower incidence of sedation, weight gain, and orthostatic hypotension though having higher rates of treatment emergent extrapyramidal symptoms.

Haloperidol acts on these receptors: (Ki)

  • D1 (silent antagonist) – Unknown efficiency.
  • D5 (silent antagonist) – Unknown efficiency.
  • D2 (inverse agonist) – 0.7 nM.
  • D3 (inverse agonist) – 0.2 nM.
  • D4 (inverse agonist) – 5–9 nM.
  • σ1 (irreversible inactivation by haloperidol metabolite HPP+) – 3 nM.
  • σ2 (agonist): 54 nM.
  • 5HT1A receptor agonist – 1927 nM.
  • 5HT2A (silent antagonist) – 53 nM.
  • 5HT2C (silent antagonist) – 10,000 nM.
  • 5HT6 (silent antagonist) – 3666 nM.
  • 5HT7 (irreversible silent antagonist) – 377.2 nM.
  • H1 (silent antagonist) – 1,800 nM.
  • M1 (silent antagonist) – 10,000 nM.
  • α1A (silent antagonist) – 12 nM.
  • α2A (silent antagonist) – 1130 nM.
  • α2B (silent antagonist) – 480 nM.
  • α2C (silent antagonist) – 550 nM.
  • NR1/NR2B subunit containing NMDA receptor (antagonist; ifenprodil site): IC50 – 2,000 nM.

Pharmacokinetics

By Mouth

The bioavailability of oral haloperidol ranges from 60-70%. However, there is a wide variance in reported mean Tmax and T1/2 in different studies, ranging from 1.7 to 6.1 hours and 14.5 to 36.7 hours respectively.

Intramuscular Injections

The drug is well and rapidly absorbed with a high bioavailability when injected intramuscularly. The Tmax is 20 minutes in healthy individuals and 33.8 minutes in patients with schizophrenia. The mean T1/2 is 20.7 hours. The decanoate injectable formulation is for intramuscular administration only and is not intended to be used intravenously. The plasma concentrations of haloperidol decanoate reach a peak at about six days after the injection, falling thereafter, with an approximate half-life of three weeks.

Intravenous Injections

The bioavailability is 100% in intravenous (IV) injection, and the very rapid onset of action is seen within seconds. The T1/2 is 14.1 to 26.2 hours. The apparent volume of distribution is between 9.5 and 21.7 L/kg. The duration of action is four to six hours.

Therapeutic Concentrations

Plasma levels of five to 15 micrograms per litre are typically seen for therapeutic response (Ulrich S, et al. Clin Pharmacokinet. 1998). The determination of plasma levels is rarely used to calculate dose adjustments but can be useful to check compliance.

The concentration of haloperidol in brain tissue is about 20-fold higher compared to blood levels. It is slowly eliminated from brain tissue, which may explain the slow disappearance of side effects when the medication is stopped.

Distribution and Metabolism

Haloperidol is heavily protein bound in human plasma, with a free fraction of only 7.5 to 11.6%. It is also extensively metabolised in the liver with only about 1% of the administered dose excreted unchanged in the urine. The greatest proportion of the hepatic clearance is by glucuronidation, followed by reduction and CYP-mediated oxidation, primarily by CYP3A4.

Society and Culture

Cost

Haloperidol is relatively inexpensive, being up to 100 fold less expensive than newer antipsychotics.

Brand Names

Haloperidol is the INN, BAN, USAN, AAN approved name.

It is sold under the tradenames Aloperidin, Bioperidolo, Brotopon, Dozic, Duraperidol (Germany), Einalon S, Eukystol, Haldol (common tradename in the US and UK), Halol, Halosten, Keselan, Linton, Peluces, Serenace and Sigaperidol.

Veterinary Use

Haloperidol is also used on many different kinds of animals for nonselective tranquilisation and diminishing behavioural arousal, in veterinary and other settings including captivity management.