On This Day … 04 October [2022]

People (Births)

  • 1929 – John E. Mack, American psychiatrist and author (d. 2004).

John E. Mack

John Edward Mack (04 October 1929 to 27 September 2004) was an American psychiatrist, writer, and professor and the head of the department of psychiatry at Harvard Medical School. In 1977, Mack won the Pulitzer Prize for his book A Prince of Our Disorder on T.E. Lawrence.

As the head of psychiatry at Harvard Medical School, Mack’s clinical expertise was in child psychology, adolescent psychology, and the psychology of religion. He was also known as a leading researcher on the psychology of teenage suicide and drug addiction, and he later became a researcher in the psychology of alien abduction experiences.

On This Day … 03 October [2022]

People (Deaths)

  • 2014 – Benedict Groeschel, American priest, psychologist, and talk show host (b. 1933).

Benedict Groeschel

Benedict Joseph Groeschel, C.F.R. (23 July 1933 to 03 October 2014) was an American Franciscan friar, Catholic priest, retreat master, author, psychologist, activist, and television host. He hosted the television talk program Sunday Night Prime (originally Sunday Night Live) broadcast on the Eternal Word Television Network, as well as several serial religious specials.

He founded the Office for Spiritual Development for the Roman Catholic Archdiocese of New York. He was Associate Director of the Trinity Retreat House for clergy and executive director of St. Francis House. He was professor of pastoral psychology at St. Joseph’s Seminary in New York and an adjunct professor at the Institute for Psychological Sciences in Arlington, Virginia. He was one of the founders of the Franciscan Friars of the Renewal and among his close friends were Mother Teresa, Mother Angelica and Alice von Hildebrand.

On This Day … 02 October [2022]

People (Deaths)

  • 2012 – J. Philippe Rushton, English-Canadian psychologist, theorist, academic (b. 1943).

J. Philippe Rushton

John Philippe Rushton (03 December 1943 to 02 October 2012) was a Canadian psychologist and author. He taught at the University of Western Ontario until the early 1990s, and became known to the general public during the 1980s and 1990s for research on race and intelligence, race and crime, and other purported racial correlations.

Rushton’s work has been heavily criticized by the scientific community for the questionable quality of its research, with many academics arguing that it was conducted under a racist agenda. From 2002 until his death, he served as the head of the Pioneer Fund, an organization founded in 1937 to promote eugenics, which has been described as racist and white supremacist in nature, and as a hate group by the Southern Poverty Law Centre. He also published articles in and spoke at conferences organized by the white supremacist magazine American Renaissance.

Rushton was a Fellow of the Canadian Psychological Association and a onetime Fellow of the John Simon Guggenheim Memorial Foundation. In 2020, the Department of Psychology of the University of Western Ontario released a statement stating that “much of [Rushton’s] research was racist”, was “deeply flawed from a scientific standpoint”, and “Rushton’s legacy shows that the impact of flawed science lingers on, even after qualified scholars have condemned its scientific integrity.” As of 2021, Rushton has had six research publications retracted.

On This Day … 01 October [2022]

People (Births)

  • 1915 – Jerome Bruner, American psychologist and author (d. 2016).

Jerome Bruner

Jerome Seymour Bruner (01 October 1915 to 05 June 2016) was an American psychologist who made significant contributions to human cognitive psychology and cognitive learning theory in educational psychology. Bruner was a senior research fellow at the New York University School of Law. He received a B.A. in 1937 from Duke University and a Ph.D. from Harvard University in 1941. He taught and did research at Harvard University, the University of Oxford, and New York University. A Review of General Psychology survey, published in 2002, ranked Bruner as the 28th most cited psychologist of the 20th century.

On This Day … 30 September [2022]

People (Births)

  • 1897 – Charlotte Wolff, German-English physician and psychotherapist (d. 1986).
  • 1911 – Gustave Gilbert, American psychologist (d. 1977).

Charlotte Wolff

Charlotte Wolff (30 September 1897 to 12 September 1986) was a German-British physician who worked as a psychotherapist and wrote on sexology and hand analysis. Her writings on lesbianism and bisexuality were influential early works in the field.

Gustave Gilbert

Gustave Mark Gilbert (30 September 1911 to 06 February 1977) was an American psychologist best known for his writings containing observations of high-ranking Nazi leaders during the Nuremberg trials. His 1950 book The Psychology of Dictatorship was an attempt to profile the Nazi German dictator Adolf Hitler using as reference the testimonials of Hitler’s closest generals and commanders. Gilbert’s published work is still a subject of study in many universities and colleges, especially in the field of psychology.

On This Day … 29 September [2022]

People (Deaths)

  • 2007 – Yıldırım Aktuna, Turkish psychiatrist and politician, Turkish Minister of Health (b. 1930).

Yildirim Aktuna

Yıldırım Aktuna (1930 to 29 September 2007) was a Turkish psychiatrist, politician, district mayor and government minister in a number of cabinets.

Early Years

He was born 1930 in Istanbul. After completing the high school in Karşıyaka, Izmir in 1948, Yıldırım Aktuna attended the School of Medicine of the University of Istanbul as a cadet. In 1954, he graduated with Doctor of Medicine degree in the rank of a lieutenant.

Military Career

His first post was chief physician officer of the 26th Brigade at the 66th Army Division. After completing a one-year English language course at the Army Language School in Ankara, Aktuna was sent to the United States, where he attended advanced education in general medicine at the Brooke Army Medical Centre in Fort Sam Houston, San Antonio between 1958-1959.

Having returned home, Aktuna specialised in neuropsychiatry at the Gülhane Military Medical Academy in Ankara, finishing in 1962. He then served in the army as medical officer at various places in Turkey. Between 1967-1989, he was lecturer at the Kabul Military Hospital in Afghanistan. In 1970, he retired from the Turkish Army in the rank of a lieutenant colonel.

Civil Service

Switched over to civil service, he firstly was appointed Assistant Chief Physician at the Psychology Clinic of Şişli Children’s Hospital in Istanbul. He later became the chief of that clinic.

Between 1972-1973, Aktuna sojourned in Austria to pursue advanced studies in neurology and electroencephalography (EEG) at the Neurological Clinic of the University of Vienna.

In 1979, Yıldırım Aktuna was appointed Chief Physician of the Bakırköy Psychiatric Hospital in Istanbul, the largest of its art in the country. He modernised the hospital, and devoted himself to raise consciousness for public mental health and to develop contemporary policies on this subject. He established in 1983 an alcohol and drug rehabilitation centre within this hospital, the first facility in Turkey to conduct medical and psychotherapeutic treatment and research for dependency on psychoactive substances as well. For these activities, he was honoured several times by various organisations.

What is Clonazepam?

Introduction

Clonazepam, sold under the brand name Klonopin among others, is a medication used to prevent and treat seizures, panic disorder, anxiety, and the movement disorder known as akathisia. It is a tranquiliser of the benzodiazepine class. It is typically taken by mouth. Effects begin within one hour and last between six and twelve hours.

Common side effects include sleepiness, poor coordination, and agitation. Long-term use may result in tolerance, dependence, and withdrawal symptoms if stopped abruptly. Dependence occurs in one-third of people who take clonazepam for longer than four weeks. There is an increased risk of suicide, particularly in people who are already depressed. If used during pregnancy it may result in harm to the foetus. Clonazepam binds to GABAA receptors, thus increasing the effect of the chief inhibitory neurotransmitter γ-aminobutyric acid (GABA).

Clonazepam was patented in 1960 and went on sale in 1975 in the United States from Roche. It is available as a generic medication. In 2019, it was the 46th most commonly prescribed medication in the United States, with more than 15 million prescriptions. In many areas of the world it is commonly used as a recreational drug.

Medical Uses

Clonazepam is prescribed for short term management of epilepsy, anxiety, and panic disorder with or without agoraphobia.

Seizures

Clonazepam, like other benzodiazepines, while being a first-line treatment for acute seizures, is not suitable for the long-term treatment of seizures due to the development of tolerance to the anticonvulsant effects.

Clonazepam has been found effective in treating epilepsy in children, and the inhibition of seizure activity seemed to be achieved at low plasma levels of clonazepam. As a result, clonazepam is sometimes used for certain rare childhood epilepsies; however, it has been found to be ineffective in the control of infantile spasms. Clonazepam is mainly prescribed for the acute management of epilepsies. Clonazepam has been found to be effective in the acute control of non-convulsive status epilepticus; however, the benefits tended to be transient in many people, and the addition of phenytoin for lasting control was required in these patients.

It is also approved for treatment of typical and atypical absences (seizures), infantile myoclonic, myoclonic, and akinetic seizures. A subgroup of people with treatment resistant epilepsy may benefit from long-term use of clonazepam; the benzodiazepine clorazepate may be an alternative due to its slow onset of tolerance.

Anxiety Disorders

  • Panic disorder with or without agoraphobia.
  • Clonazepam has also been found effective in treating other anxiety disorders, such as social phobia, but this is an off-label use.

The effectiveness of clonazepam in the short-term treatment of panic disorder has been demonstrated in controlled clinical trials. Some long-term trials have suggested a benefit of clonazepam for up to three years without the development of tolerance but these trials were not placebo-controlled. Clonazepam is also effective in the management of acute mania.

Muscle Disorders

Restless legs syndrome can be treated using clonazepam as a third-line treatment option as the use of clonazepam is still investigational. Bruxism also responds to clonazepam in the short-term. Rapid eye movement sleep behaviour disorder responds well to low doses of clonazepam.

  • The treatment of acute and chronic akathisia induced by neuroleptics, also called antipsychotics.
  • Spasticity related to amyotrophic lateral sclerosis.
  • Alcohol withdrawal syndrome

Other

  • Benzodiazepines, such as clonazepam, are sometimes used for the treatment of mania or acute psychosis-induced aggression. In this context, benzodiazepines are given either alone, or in combination with other first-line drugs such as lithium, haloperidol, or risperidone. The effectiveness of taking benzodiazepines along with antipsychotic medication is unknown, and more research is needed to determine if benzodiazepines are more effective than antipsychotics when urgent sedation is required.
  • Hyperekplexia: A very rare neurologic disorder classically characterised by pronounced startle responses to tactile or acoustic stimuli and hypertonia.
  • Many forms of parasomnia and other sleep disorders are treated with clonazepam..
  • It is not effective for preventing migraines.

Contraindications

  • Coma.
  • Current alcohol use disorder.
  • Current substance use disorder.
  • Respiratory depression.

Adverse Effects

In September 2020, the US Food and Drug Administration (FDA) required the boxed warning be updated for all benzodiazepine medicines to describe the risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions consistently across all the medicines in the class.

Common

  • Sedation.
  • Motor impairment.

Less Common

  • Confusion.
  • Irritability and aggression.
  • Psychomotor agitation.
  • Lack of motivation.
  • Loss of libido.
  • Impaired motor function.
  • Impaired coordination.
  • Impaired balance.
  • Dizziness.
  • Cognitive impairments.
  • Hallucinations.
  • Short-term memory loss.
  • Anterograde amnesia (common with higher doses).
  • Some users report hangover-like symptoms of drowsiness, headaches, sluggishness, and irritability upon waking up if the medication was taken before sleep.
    • This is likely the result of the medication’s long half-life, which continues to affect the user after waking up.
    • While benzodiazepines induce sleep, they tend to reduce the quality of sleep by suppressing or disrupting REM sleep.
    • After regular use, rebound insomnia may occur when discontinuing clonazepam.
  • Benzodiazepines may cause or worsen depression.

Occasional

  • Dysphoria.
  • Induction of seizures or increased frequency of seizures.
  • Personality changes.
  • Behavioural disturbances.
  • Ataxia.

Rare

  • Cognitive Euphoria.
  • Suicide through disinhibition.
  • Psychosis.
  • Incontinence.
  • Liver damage.
  • Paradoxical behavioural disinhibition (most frequently in children, the elderly, and in persons with developmental disabilities).
  • Rage.
  • Excitement.
  • Impulsivity.
  • The long-term effects of clonazepam can include depression, disinhibition, and sexual dysfunction.

Drowsiness

Clonazepam, like other benzodiazepines, may impair a person’s ability to drive or operate machinery. The central nervous system depressing effects of the drug can be intensified by alcohol consumption, and therefore alcohol should be avoided while taking this medication. Benzodiazepines have been shown to cause dependence. Patients dependent on clonazepam should be slowly titrated off under the supervision of a qualified healthcare professional to reduce the intensity of withdrawal or rebound symptoms.

Withdrawal-Related

  • Anxiety.
  • Irritability.
  • Insomnia.
  • Tremors.
  • Headaches.
  • Stomach pain.
  • Hallucinations.
  • Suicidal thoughts or urges.
  • Depression.
  • Fatigue.
  • Dizziness.
  • Sweating.
  • Confusion.
  • Potential to exacerbate existing panic disorder upon discontinuation.
  • Seizures similar to delirium tremens (with long-term use of excessive doses).

Benzodiazepines such as clonazepam can be very effective in controlling status epilepticus, but, when used for longer periods of time, some potentially serious side-effects may develop, such as interference with cognitive functions and behaviour. Many individuals treated on a long-term basis develop a dependence. Physiological dependence was demonstrated by flumazenil-precipitated withdrawal. Use of alcohol or other central nervous system (CNS)-depressants while taking clonazepam greatly intensifies the effects (and side effects) of the drug.

A recurrence of symptoms of the underlying disease should be separated from withdrawal symptoms.

Tolerance and Withdrawal

Refer to Benzodiazepine Withdrawal Syndrome.

Like all benzodiazepines, clonazepam is a GABA-positive allosteric modulator. One-third of individuals treated with benzodiazepines for longer than four weeks develop a dependence on the drug and experience a withdrawal syndrome upon dose reduction. High dosage and long-term use increase the risk and severity of dependence and withdrawal symptoms. Withdrawal seizures and psychosis can occur in severe cases of withdrawal, and anxiety and insomnia can occur in less severe cases of withdrawal. A gradual reduction in dosage reduces the severity of the benzodiazepine withdrawal syndrome. Due to the risks of tolerance and withdrawal seizures, clonazepam is generally not recommended for the long-term management of epilepsies. Increasing the dose can overcome the effects of tolerance, but tolerance to the higher dose may occur and adverse effects may intensify. The mechanism of tolerance includes receptor desensitisation, down regulation, receptor decoupling, and alterations in subunit composition and in gene transcription coding.

Tolerance to the anticonvulsant effects of clonazepam occurs in both animals and humans. In humans, tolerance to the anticonvulsant effects of clonazepam occurs frequently. Chronic use of benzodiazepines can lead to the development of tolerance with a decrease of benzodiazepine binding sites. The degree of tolerance is more pronounced with clonazepam than with chlordiazepoxide. In general, short-term therapy is more effective than long-term therapy with clonazepam for the treatment of epilepsy. Many studies have found that tolerance develops to the anticonvulsant properties of clonazepam with chronic use, which limits its long-term effectiveness as an anticonvulsant.

Abrupt or over-rapid withdrawal from clonazepam may result in the development of the benzodiazepine withdrawal syndrome, causing psychosis characterised by dysphoric manifestations, irritability, aggressiveness, anxiety, and hallucinations. Sudden withdrawal may also induce the potentially life-threatening condition, status epilepticus. Anti-epileptic drugs, benzodiazepines such as clonazepam in particular, should be reduced in dose slowly and gradually when discontinuing the drug to mitigate withdrawal effects. Carbamazepine has been tested in the treatment of clonazepam withdrawal but was found to be ineffective in preventing clonazepam withdrawal-induced status epilepticus from occurring.

Overdose

Refer to Benzodiazepine Overdose.

Excess doses may result in:

  • Difficulty staying awake.
  • Mental confusion.
  • Impaired motor functions.
  • Impaired reflexes.
  • Impaired coordination.
  • Impaired balance.
  • Dizziness.
  • Respiratory depression.
  • Low blood pressure.
  • Coma.

Coma can be cyclic, with the individual alternating from a comatose state to a hyper-alert state of consciousness, which occurred in a four-year-old boy who overdosed on clonazepam. The combination of clonazepam and certain barbiturates (for example, amobarbital), at prescribed doses has resulted in a synergistic potentiation of the effects of each drug, leading to serious respiratory depression.

Overdose symptoms may include extreme drowsiness, confusion, muscle weakness, and fainting.

Detection in Biological Fluids

Clonazepam and 7-aminoclonazepam may be quantified in plasma, serum, or whole blood in order to monitor compliance in those receiving the drug therapeutically. Results from such tests can be used to confirm the diagnosis in potential poisoning victims or to assist in the forensic investigation in a case of fatal overdosage. Both the parent drug and 7-aminoclonazepam are unstable in biofluids, and therefore specimens should be preserved with sodium fluoride, stored at the lowest possible temperature and analysed quickly to minimise losses.

Special Precautions

The elderly metabolise benzodiazepines more slowly than younger people and are also more sensitive to the effects of benzodiazepines, even at similar blood plasma levels. Doses for the elderly are recommended to be about half of that given to younger adults and are to be administered for no longer than two weeks. Long-acting benzodiazepines such as clonazepam are not generally recommended for the elderly due to the risk of drug accumulation.

The elderly are especially susceptible to increased risk of harm from motor impairments and drug accumulation side effects. Benzodiazepines also require special precaution if used by individuals that may be pregnant, alcohol- or drug-dependent, or may have comorbid psychiatric disorders. Clonazepam is generally not recommended for use in elderly people for insomnia due to its high potency relative to other benzodiazepines.

Clonazepam is not recommended for use in those under 18. Use in very young children may be especially hazardous. Of anticonvulsant drugs, behavioural disturbances occur most frequently with clonazepam and phenobarbital.

Doses higher than 0.5-1 mg per day are associated with significant sedation.

Clonazepam may aggravate hepatic porphyria.

Clonazepam is not recommended for patients with chronic schizophrenia. A 1982 double-blinded, placebo-controlled study found clonazepam increases violent behaviour in individuals with chronic schizophrenia.

Clonazepam has similar effectiveness to other benzodiazepines at often a lower dose.

Interactions

Clonazepam decreases the levels of carbamazepine, and, likewise, clonazepam’s level is reduced by carbamazepine. Azole antifungals, such as ketoconazole, may inhibit the metabolism of clonazepam. Clonazepam may affect levels of phenytoin (diphenylhydantoin). In turn, Phenytoin may lower clonazepam plasma levels by increasing the speed of clonazepam clearance by approximately 50% and decreasing its half-life by 31%. Clonazepam increases the levels of primidone and phenobarbital.

Combined use of clonazepam with certain antidepressants, anticonvulsants (such as phenobarbital, phenytoin, and carbamazepine), sedative antihistamines, opiates, and antipsychotics, nonbenzodiazepines (such as zolpidem), and alcohol may result in enhanced sedative effects.

Pregnancy

There is some medical evidence of various malformations (for example, cardiac or facial deformations when used in early pregnancy); however, the data is not conclusive. The data are also inconclusive on whether benzodiazepines such as clonazepam cause developmental deficits or decreases in IQ in the developing foetus when taken by the mother during pregnancy. Clonazepam, when used late in pregnancy, may result in the development of a severe benzodiazepine withdrawal syndrome in the neonate. Withdrawal symptoms from benzodiazepines in the neonate may include hypotonia, apnoeic spells, cyanosis, and impaired metabolic responses to cold stress.

The safety profile of clonazepam during pregnancy is less clear than that of other benzodiazepines, and if benzodiazepines are indicated during pregnancy, chlordiazepoxide and diazepam may be a safer choice. The use of clonazepam during pregnancy should only occur if the clinical benefits are believed to outweigh the clinical risks to the foetus. Caution is also required if clonazepam is used during breastfeeding. Possible adverse effects of use of benzodiazepines such as clonazepam during pregnancy include: miscarriage, malformation, intrauterine growth retardation, functional deficits, carcinogenesis, and mutagenesis. Neonatal withdrawal syndrome associated with benzodiazepines include hypertonia, hyperreflexia, restlessness, irritability, abnormal sleep patterns, inconsolable crying, tremors, or jerking of the extremities, bradycardia, cyanosis, suckling difficulties, apnoea, risk of aspiration of feeds, diarrhoea and vomiting, and growth retardation. This syndrome can develop between three days to three weeks after birth and can have a duration of up to several months. The pathway by which clonazepam is metabolised is usually impaired in newborns. If clonazepam is used during pregnancy or breastfeeding, it is recommended that serum levels of clonazepam are monitored and that signs of central nervous system depression and apnoea are also checked for. In many cases, non-pharmacological treatments, such as relaxation therapy, psychotherapy, and avoidance of caffeine, can be an effective and safer alternative to the use of benzodiazepines for anxiety in pregnant women.

Pharmacology

Mechanism of Action

Clonazepam enhances the activity of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in the central nervous system to give its anticonvulsant, skeletal muscle relaxant, and anxiolytic effects. It acts by binding to the benzodiazepine site of the GABA receptors, which enhances the electric effect of GABA binding on neurons, resulting in an increased influx of chloride ions into the neurons. This further results in an inhibition of synaptic transmission across the central nervous system.

Benzodiazepines do not have any effect on the levels of GABA in the brain. Clonazepam has no effect on GABA levels and has no effect on gamma-aminobutyric acid transaminase. Clonazepam does, however, affect glutamate decarboxylase activity. It differs from other anticonvulsant drugs it was compared to in a study.

Clonazepam’s primary mechanism of action is the modulation of GABA function in the brain, by the benzodiazepine receptor, located on GABAA receptors, which, in turn, leads to enhanced GABAergic inhibition of neuronal firing. Benzodiazepines do not replace GABA, but instead enhance the effect of GABA at the GABAA receptor by increasing the opening frequency of chloride ion channels, which leads to an increase in GABA’s inhibitory effects and resultant central nervous system depression. In addition, clonazepam decreases the utilisation of 5-HT (serotonin) by neurons and has been shown to bind tightly to central-type benzodiazepine receptors. Because clonazepam is effective in low milligram doses (0.5 mg clonazepam = 10 mg diazepam), it is said to be among the class of “highly potent” benzodiazepines. The anticonvulsant properties of benzodiazepines are due to the enhancement of synaptic GABA responses, and the inhibition of sustained, high-frequency repetitive firing.

Benzodiazepines, including clonazepam, bind to mouse glial cell membranes with high affinity. Clonazepam decreases release of acetylcholine in the feline brain and decreases prolactin release in rats. Benzodiazepines inhibit cold-induced thyroid-stimulating hormone (also known as TSH or thyrotropin) release. Benzodiazepines act via micromolar benzodiazepine binding sites as Ca2+ channel blockers and significantly inhibit depolarisation-sensitive calcium uptake in experimentation on rat brain cell components. This has been conjectured as a mechanism for high-dose effects on seizures in the study.

Clonazepam is a 2′-chlorinated derivative of nitrazepam, which increases its potency due to electron-attracting effect of the halogen in the ortho-position.

Pharmacokinetics

Clonazepam is lipid-soluble, rapidly crosses the blood-brain barrier, and penetrates the placenta. It is extensively metabolised into pharmacologically inactive metabolites, with only 2% of the unchanged drug excreted in the urine. Clonazepam is metabolised extensively via nitroreduction by cytochrome P450 enzymes, including CYP3A4. Erythromycin, clarithromycin, ritonavir, itraconazole, ketoconazole, nefazodone, cimetidine, and grapefruit juice are inhibitors of CYP3A4 and can affect the metabolism of benzodiazepines. It has an elimination half-life of 19-60 hours. Peak blood concentrations of 6.5-13.5 ng/mL were usually reached within 1-2 hours following a single 2 mg oral dose of micronized clonazepam in healthy adults. In some individuals, however, peak blood concentrations were reached at 4-8 hours.

Clonazepam passes rapidly into the central nervous system, with levels in the brain corresponding with levels of unbound clonazepam in the blood serum. Clonazepam plasma levels are very unreliable amongst patients. Plasma levels of clonazepam can vary as much as tenfold between different patients.

Clonazepam has plasma protein binding of 85%. Clonazepam passes through the blood-brain barrier easily, with blood and brain levels corresponding equally with each other. The metabolites of clonazepam include 7-aminoclonazepam, 7-acetaminoclonazepam and 3-hydroxy clonazepam. These metabolites are excreted by the kidney.

It is effective for 6-8 hours in children, and 6-12 in adults.

Society and Culture

Recreational Use

Refer to Benzodiazepine Misuse.

A 2006 US government study of hospital emergency department (ED) visits found that sedative-hypnotics were the most frequently implicated pharmaceutical drug in visits, with benzodiazepines accounting for the majority of these. Clonazepam was the second most frequently implicated benzodiazepine in ED visits. Alcohol alone was responsible for over twice as many ED visits as clonazepam in the same study. The study examined the number of times the non-medical use of certain drugs was implicated in an ED visit. The criteria for non-medical use in this study were purposefully broad, and include, for example, drug abuse, accidental or intentional overdose, or adverse reactions resulting from legitimate use of the medication.

Formulations

Clonazepam was approved in the United States as a generic drug in 1997 and is now manufactured and marketed by several companies.

Clonazepam is available as tablets and orally disintegrating tablets (wafers) an oral solution (drops), and as a solution for injection or intravenous infusion.

Brand Names

It is marketed under the trade name Rivotril by Roche in Argentina, Australia, Austria, Bangladesh, Belgium, Brazil, Bulgaria, Canada, Colombia, Costa Rica, Croatia, the Czech Republic, Denmark, Estonia,[136] Germany, Hungary, Iceland, Ireland, Italy, China, Mexico, the Netherlands, Norway, Portugal, Peru, Pakistan, Romania, Serbia, South Africa, South Korea, Spain, Turkey, and the United States; Emcloz, Linotril and Clonotril in India and other parts of Europe; under the name Riklona in Indonesia and Malaysia; and under the trade name Klonopin by Roche in the United States. Other names, such as Clonoten, Ravotril, Rivotril, Iktorivil, Clonex (Israel), Paxam, Petril, Naze, Zilepam and Kriadex, are known throughout the world.

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

On This Day … 27 September [2022]

People (Births)

  • 1913 – Albert Ellis, American psychologist and author (d. 2007).

People (Deaths)

  • 2004 – John E. Mack, American psychiatrist and author (b. 1929).

Albert Ellis

Albert Ellis (27 September 1913 to 24 July 2007) was an American psychologist and psychotherapist who founded rational emotive behaviour therapy (REBT). He held MA and PhD degrees in clinical psychology from Columbia University, and was certified by the American Board of Professional Psychology (ABPP). He also founded, and was the President of, the New York City-based Albert Ellis Institute. He is generally considered to be one of the originators of the cognitive revolutionary paradigm shift in psychotherapy and an early proponent and developer of cognitive-behavioural therapies.

Based on a 1982 professional survey of US and Canadian psychologists, he was considered the second most influential psychotherapist in history (Carl Rogers ranked first in the survey; Sigmund Freud was ranked third). Psychology Today noted that, “No individual—not even Freud himself—has had a greater impact on modern psychotherapy.”

John E. Mack

John Edward Mack (04 October 1929 to 27 September 2004) was an American psychiatrist, writer, and professor and the head of the department of psychiatry at Harvard Medical School. In 1977, Mack won the Pulitzer Prize for his book A Prince of Our Disorder on T.E. Lawrence.

As the head of psychiatry at Harvard Medical School, Mack’s clinical expertise was in child psychology, adolescent psychology, and the psychology of religion. He was also known as a leading researcher on the psychology of teenage suicide and drug addiction, and he later became a researcher in the psychology of alien abduction experiences.

What is Butriptyline?

Introduction

Butriptyline, sold under the brand name Evadyne among others, is a tricyclic antidepressant (TCA) that has been used in the United Kingdom and several other European countries for the treatment of depression but appears to no longer be marketed. Along with trimipramine, iprindole, and amoxapine, it has been described as an “atypical” or “second-generation” TCA due to its relatively late introduction and atypical pharmacology. It was very little-used compared to other TCAs, with the number of prescriptions dispensed only in the thousands.

Brief History

Butriptyline was developed by Wyeth, an American pharmaceutical company, and introduced in the United Kingdom in either 1974 or 1975.

Medical Uses

Butriptyline was used in the treatment of depression. It was usually used at dosages of 150-300 mg/day.

Side Effects

Butriptyline is closely related to amitriptyline, and produces similar effects as other TCAs, but its side effects like sedation are said to be reduced in severity and it has a lower risk of interactions with other medications.

Butriptyline has potent antihistamine effects, resulting in sedation and somnolence. It also has potent anticholinergic effects, resulting in side effects like dry mouth, constipation, urinary retention, blurred vision, and cognitive/memory impairment. The drug has relatively weak effects as an alpha-1 blocker and has no effects as a norepinephrine reuptake inhibitor, so is associated with little to no antiadrenergic and adrenergic side effects.

Overdose

Refer to Tricyclic Antidepressant Overdose.

Pharmacology

Pharmacodynamics

In vitro, butriptyline is a strong antihistamine and anticholinergic, moderate 5-HT2 and α1-adrenergic receptor antagonist, and very weak or negligible monoamine reuptake inhibitor. These actions appear to confer a profile similar to that of iprindole and trimipramine with serotonin-blocking effects as the apparent predominant mediator of mood-lifting efficacy.

However, in small clinical trials, using similar doses, butriptyline was found to be similarly effective to amitriptyline and imipramine as an antidepressant, despite the fact that both of these TCAs are far stronger as both 5-HT2 antagonists and serotonin–norepinephrine reuptake inhibitors. As a result, it may be that butriptyline has a different mechanism of action, or perhaps functions as a prodrug in the body to a metabolite with different pharmacodynamics.

Pharmacokinetics

Therapeutic concentrations of butriptyline are in the range of 60-280 ng/mL (204-954 nmol/L). Its plasma protein binding is greater than 90%.

Chemistry

Butriptyline is a tricyclic compound, specifically a dibenzocycloheptadiene, and possesses three rings fused together with a side chain attached in its chemical structure. Other dibenzocycloheptadiene TCAs include amitriptyline, nortriptyline, and protriptyline. Butriptyline is an analogue of amitriptyline with an isobutyl side chain instead of a propylidene side chain. It is a tertiary amine TCA, with its side chain-demethylated metabolite norbutriptyline being a secondary amine. Other tertiary amine TCAs include amitriptyline, imipramine, clomipramine, dosulepin (dothiepin), doxepin, and trimipramine. The chemical name of butriptyline is 3-(10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-yl)-N,N,2-trimethylpropan-1-amine and its free base form has a chemical formula of C21H27N with a molecular weight of 293.446 g/mol. The drug has been used commercially both as the free base and as the hydrochloride salt. The CAS Registry Number of the free base is 15686-37-0 and of the hydrochloride is 5585-73-9.

Society and Culture

Generic Names

Butriptyline is the English and French generic name of the drug and its International Non-Propriety Name (INN), British Approved Name (BAN), and Denomination Commune Francaise (DCF), while butriptyline hydrochloride is its BANM and (United States Adopted Name (USAN). Its generic name in Latin is butriptylinum, in German is butriptylin, and in Spanish is butriptylina.

Brand Names

Butriptyline has been marketed under the brand names Evadene, Evadyne, Evasidol, and Centrolese.

Availability

Butriptyline has been marketed in Europe, including in the United Kingdom, Belgium, Luxembourg, Austria, and Italy.

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What is Bromazolam?

Introduction

Bromazolam (XLI-268) is a triazolobenzodiazepine (TBZD) which was first synthesised in 1976, but was never marketed. It has subsequently been sold as a designer drug, first being definitively identified by the EMCDDA in Sweden in 2016.

Outline

It is the bromo instead of chloro analogue of alprazolam and has similar sedative and anxiolytic effects to it and other benzodiazepines. Bromazolam is a non subtype selective agonist at the benzodiazepine site of GABAA receptors, with a binding affinity of 2.81nM at the α1 subtype, 0.69nM at α2 and 0.62nM at α5.

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