Posts

What is Ethylphenidate?

Introduction

Ethylphenidate (EPH) is a psychostimulant and a close analogue of methylphenidate.

Ethylphenidate acts as both a dopamine reuptake inhibitor and norepinephrine reuptake inhibitor, meaning it effectively boosts the levels of the norepinephrine and dopamine neurotransmitters in the brain, by binding to, and partially blocking the transporter proteins that normally remove those monoamines from the synaptic cleft.

However, considering the close similarities between ethylphenidate and methylphenidate and the fact that methylphenidate, like cocaine, actually does not primarily act as a “classical” reuptake inhibitor, but rather as an “inverse agonist at the DAT” (also called a “negative allosteric modulator at the DAT”), it is at least very likely that ethylphenidate also primarily acts as an inverse DAT agonist instead of (or at least only secondarily) as a classical reuptake inhibitor (which could be called a “competitive antagonist at the DAT” using a similar terminology as “negative allosteric modulator at the DAT”, which per definition means that its mechanism is non-competitive).

Pharmacology

Pharmacokinetics

Ethylphenidate metabolises into methylphenidate and ritalinic acid.

Tiny amounts of ethylphenidate can be formed in vivo when ethanol and methylphenidate are coingested, via hepatic transesterification. Ethylphenidate formation appears to be more common when large quantities of methylphenidate and alcohol are consumed at the same time, such as in non-medical use or overdose scenarios. However, the transesterfication process of methylphenidate to ethylphenidate, as tested in mice liver, was dominant in the inactive (−)-enantiomer but showed a prolonged and increased maximal plasma concentration of the active (+)-enantiomer of methylphenidate. Additionally, only a small percent of the consumed methylphenidate is converted to ethylphenidate.

This carboxylesterase-dependent transesterification process is also known to occur when cocaine and alcohol are consumed together, forming cocaethylene.

Pharmacodynamics

All available data on ethylphenidate’s pharmacodynamics are drawn from studies conducted on rodents. Ethylphenidate is more selective to the dopamine transporter (DAT) than methylphenidate, having approximately the same efficacy as the parent compound, but has significantly less activity on the norepinephrine transporter (NET). Its dopaminergic pharmacodynamic profile is nearly identical to methylphenidate, and is primarily responsible for its euphoric and reinforcing effects.

The eudysmic ratio for ethylphenidate is superior to that of methylphenidate.

Legality

  • Ethylphenidate is a schedule II drug under the Convention on Psychotropic Substances.
  • Ethylphenidate is illegal in the Netherlands, as the Opium Law Lijst I covers it, as of 27 April 2018.
  • Ethylphenidate is not explicitly controlled in the US as part of the Controlled Substances Act but it could possibly be considered an analogue of a Schedule II substance (methylphenidate) under the Federal Analog Act if sold for human consumption.
    • In the United States, on 22 September 2023, the DEA filed a proposed rule for placement of Ethylphenidate into Schedule I status.
    • Public commenting opened on 22 September 2023, and closed on 21 November 2023.
  • Ethylphenidate is illegal in Sweden as of 15 December 2012.
  • Ethylphenidate is illegal to manufacture, distribute or import in the UK, as of 10 April 2015 it has been placed under a Temporary Class Drug Order which automatically places it in a Class-B-like category. Though ordinarily the TCDO would only last 1 year, the ACMD reported that since its invocation prevalence of MPA had significantly decreased, and that it had been challenging to collect information about the drug. As a result of this, they requested that the TCDO be extended a further year from 26 June 2016.
  • Ethylphenidate is illegal in Jersey under the Misuse of Drugs (Jersey) Law 1978.
  • Australian state and federal legislation contains provisions that mean that analogues of controlled drugs are also covered by the legislation. Ethylphenidate would be an analogue of methylphenidate under this legislation.
  • Ethylphenidate is controlled in Canada under the Controlled Drugs and Substances Act under Schedule III as of 05 May 2017.
  • Ethylphenidate is illegal in Germany as of 05 July 2013.
  • Ethylphenidate is illegal in Austria by the “Neue Psychoaktive Substanzen Gesetz” (=new psychoactive substances act) NPSG since 01 January 2012
  • Ethylphenidate is illegal in Denmark as of 01 February 2013.
  • Ethylphenidate is illegal in Poland by “the Act on Counteracting Drug Addiction” since 01 July 2015.
  • It is illegal in Lithuania to use, buy, possess, transport, sell or import Ethylphenidate from 2015.
  • As of October 2015 Ethylphenidate is a controlled substance in China.
  • In Finland ethylphenidate is scheduled in government decree on substances, preparations and plants considered to be narcotic drugs.

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

What is Dexmethylphenide?

Introduction

Dexmethylphenidate, sold under the brand name Focalin among others, is a potent central nervous system (CNS) stimulant used to treat attention deficit hyperactivity disorder (ADHD) in those over the age of five years. It is taken by mouth. The immediate release formulation lasts up to five hours while the extended release formulation lasts up to twelve hours. It is the more active enantiomer of methylphenidate.

Common side effects include abdominal pain, loss of appetite, and fever. Serious side effects may include abuse, psychosis, sudden cardiac death, mania, anaphylaxis, seizures, and dangerously prolonged erection. Safety during pregnancy and breastfeeding is unclear. Dexmethylphenidate is a central nervous system (CNS) stimulant. How it works in ADHD is unclear.

Dexmethylphenidate was approved for medical use in the United States in 2001. It is available as a generic medication. In 2020, it was the 130th most commonly prescribed medication in the United States, with more than 4 million prescriptions.

Medical Uses

Dexmethylphenidate is used as a treatment for ADHD, usually along with psychological, educational, behavioural or other forms of treatment. It is proposed that stimulants help ameliorate the symptoms of ADHD by making it easier for the user to concentrate, avoid distraction, and control behaviour. Placebo-controlled trials have shown that once-daily dexmethylphenidate XR was effective and generally well tolerated.

Improvements in ADHD symptoms in children were significantly greater for dexmethylphenidate XR versus placebo. It also showed greater efficacy than osmotic controlled-release oral delivery system (OROS) methylphenidate over the first half of the laboratory classroom day but assessments late in the day favoured OROS methylphenidate.

Contraindications

Methylphenidate is contraindicated for individuals using monoamine oxidase inhibitors (e.g., phenelzine, and tranylcypromine), or individuals with agitation, tics, glaucoma, heart defects or a hypersensitivity to any ingredients contained in methylphenidate pharmaceuticals.

Pregnant women are advised to only use the medication if the benefits outweigh the potential risks. Not enough human studies have been conducted to conclusively demonstrate an effect of methylphenidate on foetal development. In 2018, a review concluded that it has not been teratogenic in rats and rabbits, and that it “is not a major human teratogen”.

Adverse Effects

Products containing dexmethylphenidate have a side effect profile comparable to those containing methylphenidate.

The most common side effects associated with methylphenidate (in standard and extended-release formulations) are appetite loss, dry mouth, anxiety/nervousness, nausea, and insomnia. Gastrointestinal adverse effects may include abdominal pain and weight loss. Nervous system adverse effects may include akathisia (agitation/restlessness), irritability, dyskinesia (tics), Oromandibular dystonia, lethargy (drowsiness/fatigue), and dizziness. Cardiac adverse effects may include palpitations, changes in blood pressure, and heart rate (typically mild), and tachycardia (rapid heart rate). Ophthalmologic adverse effects may include blurred vision caused by pupil dilatation and dry eyes, with less frequent reports of diplopia and mydriasis.

Smokers with ADHD who take methylphenidate may increase their nicotine dependence, and smoke more often than before they began using methylphenidate, with increased nicotine cravings and an average increase of 1.3 cigarettes per day.

There is some evidence of mild reductions in height with prolonged treatment in children. This has been estimated at 1 centimetre (0.4 in) or less per year during the first three years with a total decrease of 3 centimetres (1.2 in) over 10 years.

Hypersensitivity (including skin rash, urticaria, and fever) is sometimes reported when using transdermal methylphenidate. The Daytrana patch has a much higher rate of skin reactions than oral methylphenidate.

Methylphenidate can worsen psychosis in people who are psychotic, and in very rare cases it has been associated with the emergence of new psychotic symptoms. It should be used with extreme caution in people with bipolar disorder due to the potential induction of mania or hypomania. There have been very rare reports of suicidal ideation, but some authors claim that evidence does not support a link. Logorrhea is occasionally reported and visual hallucinations are very rarely reported. Priapism is a very rare adverse event that can be potentially serious.

US Food and Drug Administration-commissioned studies in 2011 indicate that in children, young adults, and adults, there is no association between serious adverse cardiovascular events (sudden death, heart attack, and stroke) and the medical use of methylphenidate or other ADHD stimulants.

Because some adverse effects may only emerge during chronic use of methylphenidate, a constant watch for adverse effects is recommended.

A 2018 Cochrane review found that methylphenidate might be associated with serious side effects such as heart problems, psychosis, and death. The certainty of the evidence was stated as very low.

The same review found tentative evidence that it may cause both serious and non-serious adverse effects in children.

Overdose

The symptoms of a moderate acute overdose on methylphenidate primarily arise from central nervous system overstimulation; these symptoms include: vomiting, nausea, agitation, tremors, hyperreflexia, muscle twitching, euphoria, confusion, hallucinations, delirium, hyperthermia, sweating, flushing, headache, tachycardia, heart palpitations, cardiac arrhythmias, hypertension, mydriasis, and dryness of mucous membranes. A severe overdose may involve symptoms such as hyperpyrexia, sympathomimetic toxidrome, convulsions, paranoia, stereotypy (a repetitive movement disorder), rhabdomyolysis, coma, and circulatory collapse. A methylphenidate overdose is rarely fatal with appropriate care. Following injection of methylphenidate tablets into an artery, severe toxic reactions involving abscess formation and necrosis have been reported.

Treatment of a methylphenidate overdose typically involves the administration of benzodiazepines, with antipsychotics, α-adrenoceptor agonists and propofol serving as second-line therapies.

Addiction and Dependence

Methylphenidate is a stimulant with an addiction liability and dependence liability similar to amphetamine. It has moderate liability among addictive drugs; accordingly, addiction and psychological dependence are possible and likely when methylphenidate is used at high doses as a recreational drug. When used above the medical dose range, stimulants are associated with the development of stimulant psychosis.

Biomolecular Mechanisms

Methylphenidate has the potential to induce euphoria due to its pharmacodynamic effect (i.e. dopamine reuptake inhibition) in the brain’s reward system. At therapeutic doses, ADHD stimulants do not sufficiently activate the reward system; consequently, when taken as directed in doses that are commonly prescribed for the treatment of ADHD, methylphenidate use lacks the capacity to cause an addiction.

Interactions

Methylphenidate may inhibit the metabolism of vitamin K anticoagulants, certain anticonvulsants, and some antidepressants (tricyclic antidepressants, and selective serotonin reuptake inhibitors). Concomitant administration may require dose adjustments, possibly assisted by monitoring of plasma drug concentrations. There are several case reports of methylphenidate inducing serotonin syndrome with concomitant administration of antidepressants.

When methylphenidate is coingested with ethanol, a metabolite called ethylphenidate is formed via hepatic transesterification, not unlike the hepatic formation of cocaethylene from cocaine and ethanol. The reduced potency of ethylphenidate and its minor formation means it does not contribute to the pharmacological profile at therapeutic doses and even in overdose cases ethylphenidate concentrations remain negligible.

Coingestion of alcohol (ethanol) also increases the blood plasma levels of d-methylphenidate by up to 40%.

Liver toxicity from methylphenidate is extremely rare, but limited evidence suggests that intake of β-adrenergic agonists with methylphenidate may increase the risk of liver toxicity.

Mode of Activity

Methylphenidate is a catecholamine reuptake inhibitor that indirectly increases catecholaminergic neurotransmission by inhibiting the dopamine transporter (DAT) and norepinephrine transporter (NET), which are responsible for clearing catecholamines from the synapse, particularly in the striatum and meso-limbic system. Moreover, it is thought to “increase the release of these monoamines into the extraneuronal space.”

Although four stereoisomers of methylphenidate (MPH) are possible, only the threo diastereoisomers are used in modern practice. There is a high eudysmic ratio between the SS and RR enantiomers of MPH. Dexmethylphenidate (d-threo-methylphenidate) is a preparation of the RR enantiomer of methylphenidate. In theory, D-TMP (d-threo-methylphenidate) can be anticipated to be twice the strength of the racemic product

Pharmacology

Dexmethylphenidate has a 4–6 hour duration of effect. A long-acting formulation, Focalin XR, which spans 12 hours is also available and has been shown to be as effective as DL (dextro-, levo-)-TMP (threo-methylphenidate) XR (extended release) (Concerta, Ritalin LA), with flexible dosing and good tolerability. It has also been demonstrated to reduce ADHD symptoms in both children and adults. d-MPH has a similar side-effect profile to MPH and can be administered without regard to food intake.

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

What is Desoxypipradrol?

Introduction

Desoxypipradrol, also known as 2-⁠diphenylmethylpiperidine (2-DPMP), is a drug developed by Ciba in the 1950s which acts as a norepinephrine-dopamine reuptake inhibitor (NDRI).

Brief History

Desoxypipradrol was developed by the pharmaceutical company CIBA (now called Novartis) in the 1950s, and researched for applications such as the treatment of narcolepsy and ADHD; however, it was dropped from development after the related drug methylphenidate was developed by the same company. Methylphenidate was felt to be the superior drug for treating ADHD due to its shorter duration of action and more predictable pharmacokinetics, and while desoxypipradrol was researched for other applications (such as facilitation of rapid recovery from anaesthesia), its development was not continued. The hydroxylated derivative pipradrol was, however, introduced as a clinical drug indicated for depression, narcolepsy and cognitive enhancement in organic dementia.

Chemistry

Desoxypipradrol is closely related on a structural level to the compounds methylphenidate and pipradrol, all three of which share a similar pharmacological action. Of these three piperidines, desoxypipradrol has the longest elimination half-life, as it is a highly lipophilic molecule lacking polar functional groups that are typically targeted by metabolic enzymes, giving it an extremely long duration of action when compared to most psychostimulants. Methylphenidate, on the other hand, is a short-acting compound, as it possesses a methyl-ester moiety that is easily cleaved, forming a highly polar acid group, while pipradrol is intermediate in duration, possessing a hydroxyl group which can be conjugated (e.g. with glucuronide) to increase its hydrophilicity and facilitate excretion, but no easily metabolised groups.

Detection in Biological Specimens

Desoxypipradrol may be quantitated in blood, plasma or urine by liquid chromatography-mass spectrometry to confirm a diagnosis of poisoning in hospitalised patients or to provide evidence in a medicolegal death investigation. Blood or plasma desoxypipradrol concentrations are expected to be in a range of 10–50 μg/L in persons using the drug recreationally, >100 μg/L in intoxicated patients and >600 μg/L in victims of acute overdosage

Legal Status

Desoxypipradrol’s structural similarity to pipradrol makes it possible that it would be considered a controlled substance analogue in several countries such as Australia and New Zealand.

China

As of October 2015 2-DPMP is a controlled substance in China.

United Kingdom

As of 04 November 2010, the UK Home Office announced a ban on the importation of 2-DPMP, following a recommendation from the Advisory Council on the Misuse of Drugs (ACMD).

Prior to the import ban, desoxypipradrol was sold as a ‘legal high’ in several products, most notably “Ivory wave”. Its use lead to several Emergency Department visits which prompted the UK government to commission a review from the ACMD. One man had ingested nearly 1 gram of the drug which may have been fatal without sedation with an anaesthetic dose of a benzodiazepine administered in accident and emergency.

The Advisory Council on the Misuse of Drugs stated in their report that:

“there are serious harms associated with 2-DPMP… typically prolonged agitation (lasting up to 5 days after drug use which is sometimes severe, requiring physical restraint), paranoia, hallucinations and myoclonus (muscle spasms/twitches).”

2-DPMP was due to become a class B drug on 28 March 2012, but the bill was scrapped as two steroids deemed not to be abusable were included in the bill but were later recommended to remain uncontrolled. There was a new discussion about its fate on 23 April 2012, where it was decided that the bill would be rewritten and 2-DPMP would still be banned. It was also decided that the bill would be a blanket ban of related chemicals.

Desoxypipradrol was eventually made a class B drug and placed in Schedule I on 13 June 2012. There were no recorded deaths from the drug between the banning of its import and the banning of its possession. “Esters and ethers of pipradrol” were controlled with the same amendment as class C drugs.

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

What is Buspirone?

Introduction

Buspirone, sold under the brand name Buspar, among others, is a medication primarily used to treat anxiety disorders, particularly generalised anxiety disorder. Benefits support its short-term use. It is taken orally (by mouth), and takes two to six weeks to be fully effective.

Refer to Azapirone.

Common side effects of buspirone include nausea, headaches, dizziness, and difficulty concentrating. Serious side effects may include movement disorders, serotonin syndrome, and seizures. Its use in pregnancy appears to be safe but has not been well studied, and use during breastfeeding has not been well studied. It is a serotonin 5-HT1A receptor agonist.

Buspirone was first made in 1968 and approved for medical use in the United States in 1986. It is available as a generic medication. In 2020, it was the 55th most-commonly prescribed medication in the United States, with more than 12 million prescriptions.

Brief History

Buspirone was first synthesized by a team at Mead Johnson in 1968 but was not patented until 1980. It was initially developed as an antipsychotic acting on the D2 receptor but was found to be ineffective in the treatment of psychosis; it was then used as an anxiolytic instead. In 1986, Bristol-Myers Squibb gained FDA approval for buspirone in the treatment of GAD. The patent expired in 2001, and buspirone is now available as a generic drug.

Medical Uses

Anxiety

Buspirone is used for the short-term and long-term treatment of anxiety disorders or symptoms of anxiety. It is generally preferred over benzodiazepines because it does not activate the receptors that make drugs like alprazolam addictive.

Buspirone has no immediate anxiolytic effects, and hence has a delayed onset of action; its full clinical effectiveness may require 2–4 weeks to manifest itself. The drug has been shown to be similarly effective in the treatment of generalised anxiety disorder (GAD) to benzodiazepines including diazepam, alprazolam, lorazepam, and clorazepate. Buspirone is not known to be effective in the treatment of other anxiety disorders besides GAD, although there is some limited evidence that it may be useful in the treatment of social phobia as an adjunct to selective serotonin reuptake inhibitors (SSRIs).

Other Uses

Sexual Dysfunction

There is some evidence that buspirone on its own may be useful in the treatment of hypoactive sexual desire disorder (HSDD) in women. Buspirone may also be effective in treating antidepressant-induced sexual dysfunction.

Miscellaneous

Buspirone is not effective as a treatment for benzodiazepine withdrawal, barbiturate withdrawal, or alcohol withdrawal/delirium tremens.

SSRI and SNRI antidepressants such as paroxetine and venlafaxine may cause jaw pain/jaw spasm reversible syndrome (although it is not common), and buspirone appears to be successful in treating bruxism on SSRI/SNRI-induced jaw clenching.

Contraindications

Buspirone has these contraindications:

  • Hypersensitivity to buspirone
  • Metabolic acidosis, as in diabetes
  • Should not be used with MAO inhibitors
  • Severely compromised liver and/or kidney function

Side Effects

Known side effects associated with buspirone include dizziness, headaches, nausea, tinnitus, and paraesthesia. Buspirone is relatively well tolerated, and is not associated with sedation, cognitive and psychomotor impairment, muscle relaxation, physical dependence, or anticonvulsant effects. In addition, buspirone does not produce euphoria and is not a drug of abuse. Dyskinesia, akathisia, myoclonus, parkinsonism, and dystonia were reported associated with buspirone. It is unclear if there is a risk of tardive dyskinesia or other movement disorders with buspirone.

Overdose

Buspirone appears to be relatively benign in cases of single-drug overdose, although no definitive data on this subject appear to be available. In one clinical trial, buspirone was administered to healthy male volunteers at a dosage of 375 mg/day, and produced side effects including nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. In early clinical trials, buspirone was given at dosages even as high as 2,400 mg/day, with akathisia, tremor, and muscle rigidity observed. Deliberate overdoses with 250 mg and up to 300 mg buspirone have resulted in drowsiness in about 50% of individuals. One death has been reported in a co-ingestion of 450 mg buspirone with alprazolam, diltiazem, alcohol, cocaine.

Interactions

Buspirone has been shown in vitro to be metabolized by the enzyme CYP3A4. This finding is consistent with the in vivo interactions observed between buspirone and these inhibitors or inducers of cytochrome P450 3A4 (CYP3A4), among others:

  • Itraconazole: Increased plasma level of buspirone
  • Rifampicin: Decreased plasma levels of buspirone
  • Nefazodone: Increased plasma levels of buspirone
  • Haloperidol: Increased plasma levels of buspirone
  • Carbamazepine: Decreased plasma levels of buspirone
  • Grapefruit: Significantly increases the plasma levels of buspirone.
  • Fluvoxamine: Moderately increase plasma levels of buspirone.
  • Elevated blood pressure has been reported when buspirone has been administered to patients taking monoamine oxidase inhibitors (MAOIs).

Pharmacology

Pharmacodynamics

Buspirone acts as an agonist of the serotonin 5-HT1A receptor with high affinity. It is a partial agonist of both presynaptic 5-HT1A receptors, which are inhibitory autoreceptors, and postsynaptic 5-HT1A receptors. It is thought that the main effects of buspirone are mediated via its interaction with the presynaptic 5-HT1A receptor, thus reducing the firing of serotonin-producing neurons. Buspirone also has lower affinities for the serotonin 5-HT2A, 5-HT2B, 5-HT2C, 5-HT6, and 5-HT7 receptors.

In addition to binding to serotonin receptors, buspirone is an antagonist of the dopamine D2 receptor with weak affinity. It preferentially blocks inhibitory presynaptic D2 autoreceptors, and antagonises postsynaptic D2 receptors only at higher doses. In accordance, buspirone has been found to increase dopaminergic neurotransmission in the nigrostriatal pathway at low doses, whereas at higher doses, postsynaptic D2 receptors are blocked and antidopaminergic effects such as hypoactivity and reduced stereotypy, though notably not catalepsy, are observed in animals. Buspirone has also been found to bind with much higher affinity to the dopamine D3 and D4 receptors, where it is similarly an antagonist.

A major metabolite of buspirone, 1-(2-pyrimidinyl)piperazine (1-PP), occurs at higher circulating levels than buspirone itself and is known to act as a potent α2-adrenergic receptor antagonist. This metabolite may be responsible for the increased noradrenergic and dopaminergic activity observed with buspirone in animals. In addition, 1-PP may play an important role in the antidepressant effects of buspirone. Buspirone also has very weak and probably clinically unimportant affinity for the α1-adrenergic receptor. However, buspirone has been reported to have shown “significant and selective intrinsic efficacy” at the α1-adrenergic receptor expressed in a “tissue- and species-dependent manner”.

Unlike benzodiazepines, buspirone does not interact with the GABAA receptor complex.

Pharmacokinetics

Buspirone has a low oral bioavailability of 3.9% relative to intravenous injection due to extensive first-pass metabolism. The time to peak plasma levels following ingestion is 0.9 to 1.5 hours. It is reported to have an elimination half-life of 2.8 hours, although a review of 14 studies found that the mean terminal half-life ranged between 2 and 11 hours, and one study even reported a terminal half-life of 33 hours. Buspirone is metabolised primarily by CYP3A4, and prominent drug interactions with inhibitors and inducers of this enzyme have been observed. Major metabolites of buspirone include 5-hydroxybuspirone, 6-hydroxybuspirone, 8-hydroxybuspirone, and 1-PP. 6-Hydroxybuspirone has been identified as the predominant hepatic metabolite of buspirone, with plasma levels that are 40-fold greater than those of buspirone after oral administration of buspirone to humans. The metabolite is a high-affinity partial agonist of the 5-HT1A receptor (Ki = 25 nM) similarly to buspirone, and has demonstrated occupancy of the 5-HT1A receptor in vivo. As such, it is likely to play an important role in the therapeutic effects of buspirone. 1-PP has also been found to circulate at higher levels than those of buspirone itself and may similarly play a significant role in the clinical effects of buspirone.

Chemistry

Buspirone is a member of the azapirone chemical class, and consists of azaspirodecanedione and pyrimidinylpiperazine components linked together by a butyl chain.

Analogues

Structural analogues of buspirone include other azapirones like gepirone, ipsapirone, perospirone, and tandospirone.

A number of analogues are recorded.

Synthesis

A number of more modern methods of synthesis have also been reported (list not exhaustive).

Alkylation of 1-(2-pyrimidyl)piperazine 20980-22-7 with 3-chloro-1-cyanopropane (4-chlorobutyronitrile) 628-20-6 gives 33386-14-0. the reduction of the nitrile group is performed either by catalytic hydrogenation or with LAH giving 33386-20-8. The primary amine is then reacted with 3,3-tetramethyleneglutaric anhydride 5662-95-3 in order to yield Buspirone (6).

Society and Culture

Generic names

Buspirone is the INNTooltip International Nonproprietary Name, BANTooltip British Approved Name, DCFTooltip Dénomination Commune Française, and DCITTooltip Denominazione Comune Italiana of buspirone, while buspirone hydrochloride is its USANTooltip United States Adopted Name, BANMTooltip British Approved Name, and JANTooltip Japanese Accepted Name.

Brand Name

Buspirone was primarily sold under the brand name Buspar. Buspar is currently listed as discontinued by the US Food and Drug Administration (FDA). In 2010, in response to a citizen petition, the FDA determined that Buspar was not withdrawn from sale for reasons of safety or effectiveness.

2019 Shortage

Due to interrupted production at a Mylan Pharmaceuticals plant in Morgantown, West Virginia, the US experienced a shortage of buspirone in 2019.

Research

Some tentative research supports other uses such as the treatment of depression and behavioural problems following brain damage.

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

What is Brexpiprazole?

Introduction

Brexpiprazole, sold under the brand name Rexulti among others, is a medication used for the treatment of major depressive disorder, schizophrenia, and agitation associated with dementia due to Alzheimer’s disease. It is an atypical antipsychotic.

The most common side effects include akathisia (a constant urge to move) and weight gain. The most common side effects among people with agitation associated with dementia due to Alzheimer’s disease include headache, dizziness, urinary tract infection, nasopharyngitis, and sleep disturbances (both somnolence and insomnia).

Brexpiprazole was developed by Otsuka and Lundbeck, and is considered to be a successor to aripiprazole (Abilify). It was approved for medical use in the United States in July 2015. A generic version was approved in August 2022. Brexpiprazole is the first treatment approved by the US Food and Drug Administration (FDA) for agitation associated with dementia due to Alzheimer’s disease.

Medical Uses

In the United States and Canada, brexpiprazole is indicated as an adjunctive therapy to antidepressants for the treatment of major depressive disorder and for the treatment of schizophrenia. In May 2023, the indication for brexpiprazole was expanded in the US to include the treatment of agitation associated with dementia due to Alzheimer’s disease.

In Australia and the European Union, brexpiprazole is indicated for the treatment of schizophrenia.

In 2020, it was approved in Brazil only as an adjunctive to the treatment of major depressive disorder.

Side Effects

The most common adverse events associated with brexpiprazole (all doses of brexpiprazole cumulatively greater than or equal to 5% vs. placebo) were upper respiratory tract infection (6.9% vs. 4.8%), akathisia (6.6% vs. 3.2%), weight gain (6.3% vs. 0.8%), and nasopharyngitis (5.0% vs. 1.6%). Brexpiprazole can cause impulse control disorders.

Pharmacology

Pharmacodynamics

Brexpiprazole acts as a partial agonist of the serotonin 5-HT1A receptor and the dopamine D2 and D3 receptors. Partial agonists have both blocking properties and stimulating properties at the receptor they bind to. The ratio of blocking activity to stimulating activity determines a portion of its clinical effects. Brexpiprazole has more blocking and less stimulating activity at the dopamine receptors than its predecessor, aripiprazole, which may decrease its risk for agitation and restlessness. Specifically, where aripiprazole has an intrinsic activity or agonist effect at the D2 receptor of 60%+, brexpiprazole has an intrinsic activity at the same receptor of about 45%. For aripiprazole, this means more dopamine receptor activation at lower doses, with blockade being reached at higher doses, while brexpiprazole has the inverse effect because a partial agonist competes with dopamine. Brexpiprazole has a high affinity for the 5-HT1A receptor, acting as a potent antagonist at 5-HT2A receptors, and a potent partial agonist at dopamine D2 receptors with lower intrinsic activity compared to aripiprazole. In vivo characterisation of brexpiprazole shows that it may act as a near-full agonist of the 5-HT1A receptor. This may further underlie a lower potential than aripiprazole to cause treatment-emergent, movement-related disorders such as akathisia due to the downstream dopamine release that is triggered by 5-HT1A receptor agonism. It is also an antagonist of the serotonin 5-HT2A, 5-HT2B, and 5-HT7 receptors, which may contribute to antidepressant effect. It also binds to and blocks the α1A-, α1B-, α1D-, and α2C-adrenergic receptors. The drug has negligible affinity for the muscarinic acetylcholine receptors, and hence has no anticholinergic effects. Although brexpiprazole has less affinity for H1 compared to aripiprazole, weight gain can occur.

Brief History

Clinical Trials

Brexpiprazole was in clinical trials for adjunctive treatment of major depressive disorder, adult attention deficit hyperactivity disorder, bipolar disorder, schizophrenia, and agitation associated with dementia due to Alzheimer’s disease.

Major Depressive Disorder

Phase II

The phase II multicenter, double-blind, placebo-controlled study randomized 429 adult MDD patients who exhibited an inadequate response to one to three approved antidepressant treatments (ADTs) in the current episode. The study was designed to assess the efficacy and safety of brexpiprazole as an adjunctive treatment to standard antidepressant treatment. The antidepressants included in the study were desvenlafaxine, escitalopram, fluoxetine, paroxetine, sertraline, and venlafaxine.

Phase III

A phase III study was in the recruiting stage: “Study of the Safety and Efficacy of Two Fixed Doses of OPC-34712 as Adjunctive Therapy in the Treatment of Adults With Major Depressive Disorder (the Polaris Trial)”. Its goal is “to compare the effect of brexpiprazole to the effect of placebo (an inactive substance) as add on treatment to an assigned FDA approved antidepressant treatment (ADT) in patients with major depressive disorder who demonstrate an incomplete response to a prospective trial of the same assigned FDA approved ADT”. Estimated enrolment was 1,250 volunteers.

Adult Attention Deficit Hyperactivity Disorder

  • Attention Deficit/Hyperactivity Disorder (STEP-A)

Schizophrenia

Phase I

  • Trial to Evaluate the Effects of OPC-34712 (brexpiprazole) on QT/QTc in Subjects With Schizophrenia or Schizoaffective Disorder

Phase II

  • A Dose-finding Trial of OPC-34712 in Patients With Schizophrenia

Phase III

  • Efficacy Study of OPC-34712 in Adults With Acute Schizophrenia (BEACON)
  • Study of the Effectiveness of Three Different Doses of OPC-34712 in the Treatment of Adults With Acute Schizophrenia (VECTOR)
  • A Long-term Trial of OPC-34712 in Patients With Schizophrenia

Agitation Associated with Dementia due to Alzheimer’s Disease

The effectiveness of brexpiprazole for the treatment of agitation associated with dementia due to Alzheimer’s disease was determined through two 12-week, randomized, double-blind, placebo-controlled, fixed-dose studies. In these studies, participants were required to have a probable diagnosis of Alzheimer’s dementia; have a score between 5 and 22 on the Mini-Mental State Examination, a test that detects whether a person is experiencing cognitive impairment; and exhibit the type, frequency, and severity of agitation behaviours that require medication. Trial participants ranged between 51 and 90 years of age.

Society and Culture

Legal Status

In January 2018, it was approved for the treatment of schizophrenia in Japan.

Economics

In November 2011, Otsuka Pharmaceutical and Lundbeck announced a global alliance. Lundbeck gave Otsuka an upfront payment of $200 million, and the deal includes development, regulatory and sales payments, for a potential total of $1.8 billion. Specifically for OPC-34712, Lundbeck will obtain 50% of net sales in Europe and Canada and 45% of net sales in the US from Otsuka.

Patents

  • US Patent 8,071,600
  • WIPO PCT/JP2006/317704
  • Canadian patent: 2620688

Research

Brexpiprazole was under development for the treatment of attention deficit hyperactivity disorder (ADHD) as an adjunct to stimulants, but was discontinued for this indication. It reached phase II clinical trials for this use prior to discontinuation.

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

What is Asenapine?

Introduction

Asenapine, sold under the brand name Saphris among others, is an atypical antipsychotic medication used to treat schizophrenia and acute mania associated with bipolar disorder as well as the medium to long-term management of bipolar disorder.

It was chemically derived via altering the chemical structure of the tetracyclic (atypical) antidepressant, mianserin.

It was initially approved in the United States in 2009 and approved as a generic medication in 2020.

Medical Uses

Asenapine has been approved by the FDA (US Food and Drug Administration) for the acute treatment of adults with schizophrenia and acute treatment of manic or mixed episodes associated with bipolar I disorder with or without psychotic features in adults. In Australia asenapine’s approved (and also listed on the PBS (Pharmaceutical Benefits Scheme)) indications include the following.

  • Schizophrenia
  • Treatment, for up to 6 months, of an episode of acute mania or mixed episodes associated with bipolar I disorder
  • Maintenance treatment, as monotherapy, of bipolar I disorder

In the European Union and the United Kingdom, asenapine is only licensed for use as a treatment for acute mania in bipolar I disorder.

Asenapine is absorbed readily if administered sublingually, asenapine is poorly absorbed when swallowed. A transdermal formulation of asenapine was approved in the United States in October 2019 under the brand name Secuado.

Schizophrenia

A Cochrane systematic review found that while Asenapine has some preliminary evidence that it improves positive, negative, and depressive symptoms, it does not have enough research to merit a certain recommendation of asenapine for the treatment of schizophrenia.

Bipolar Disorder

For the medium-term and long-term management and control of both depressive and manic features of bipolar disorder asenapine was found be equally effective as olanzapine, but with a substantially superior side effect profile.

In acute mania, asenapine was found to be significantly superior to placebo. As for its efficacy in the treatment of acute mania, a recent meta-analysis showed that it produces comparatively small improvements in manic symptoms in patients with acute mania and mixed episodes than most other antipsychotic drugs such as risperidone and olanzapine (with the exception of ziprasidone). Drop-out rates (in clinical trials) were also unusually high with asenapine. According to a post-hoc analysis of two 3-week clinical trials it may possess some antidepressant effects in patients with acute mania or mixed episodes.

Adverse Effects

Adverse Effect Incidence

  • Very common (>10% incidence) adverse effects include:
    • Somnolence
  • Common (1-10% incidence) adverse effects include:
    • Weight gain
    • Increased appetite
    • Extrapyramidal side effects (EPS; such as dystonia, akathisia, dyskinesia, muscle rigidity, parkinsonism)
    • Sedation
    • Dizziness
    • Dysgeusia (altered taste)
    • Oral hypoaesthesia (numbness)
    • Increased alanine aminotransferase
    • Fatigue
  • Uncommon (0.1-1% incidence) adverse effects include:
    • Hyperglycaemia — elevated blood glucose (sugar)
    • Syncope
    • Seizure
    • Dysarthria
    • sinus bradycardia
    • Bundle branch block
    • QTc interval prolongation (has a relatively low risk for causing QTc interval prolongation.[17][18])
    • sinus tachycardia
    • Orthostatic hypotension
    • Hypotension
    • Swollen tongue
    • Dysphagia (difficulty swallowing)
    • Glossodynia
    • Oral paraesthesia
  • Rare (0.01-0.1% incidence) adverse effects include:
    • Neuroleptic malignant syndrome (Combination of fever, muscle stiffness, faster breathing, sweating, reduced consciousness, and sudden change in blood pressure and heart rate)
    • Tardive dyskinesia
    • Speech disturbance
    • Rhabdomyolysis
    • Angioedema
    • Blood dyscrasias such as agranulocytosis, leukopenia and neutropenia
    • Accommodation disorder[clarification needed]
    • Pulmonary embolism
    • Gynaecomastia
    • Galactorrhoea
  • Unknown incidence adverse effects:
    • Allergic reaction
    • Restless legs syndrome
    • Nausea
    • Oral mucosal lesions (ulcerations, blistering and inflammation)
    • Salivary hypersecretion
    • Hyperprolactinaemia

Asenapine seems to have a relatively low weight gain liability for an atypical antipsychotic (which are notorious for their metabolic side effects) and a 2013 meta-analysis found significantly less weight gain (SMD [standard mean difference in weight gained in those on placebo vs. active drug]: 0.23; 95% CI: 0.07-0.39) than, paliperidone (SMD: 0.38; 95% CI: 0.27-0.48), risperidone (SMD: 0.42; 95% CI: 0.33-0.50), quetiapine (SMD: 0.43; 95% CI: 0.34-0.53), sertindole (SMD: 0.53; 95% CI: 0.38-0.68), chlorpromazine (SMD: 0.55; 95% CI: 0.34-0.76), iloperidone (SMD: 0.62; 95% CI: 0.49-0.74), clozapine (SMD: 0.65; 95% CI: 0.31-0.99), zotepine (SMD: 0.71; 95% CI: 0.47-0.96) and olanzapine (SMD: 0.74; 95% CI: 0.67-0.81) and approximately (that is, no statistically significant difference at the p=0.05 level) as much as weight gain as aripiprazole (SMD: 0.17; 95% CI: 0.05-0.28), lurasidone (SMD: 0.10; 95% CI: –0.02-0.21), amisulpride (SMD: 0.20; 95% CI: 0.05-0.35), haloperidol (SMD: 0.09; 95% CI: 0.00-0.17) and ziprasidone (SMD: 0.10; 95% CI: –0.02-0.22).

Its potential for elevating plasma prolactin levels seems relatively limited too according to this meta-analysis. This meta-analysis also found that asenapine has approximately the same odds ratio (3.28; 95% CI: 1.37-6.69) for causing sedation [compared to placebo-treated patients] as olanzapine (3.34; 95% CI: 2.46-4.50]) and haloperidol (2.76; 95% CI: 2.04-3.66) and a higher odds ratio (although not significantly) for sedation than aripiprazole (1.84; 95% CI: 1.05-3.05), paliperidone (1.40; 95% CI: 0.85-2.19) and amisulpride (1.42; 95% CI: 0.72 to 2.51) to name a few and is hence a mild-moderately sedating antipsychotic. The same meta-analysis suggested that asenapine had a relatively high risk of extrapyramidal symptoms compared to other atypical antipsychotics but a lower risk than first-generation or typical antipsychotics.

Discontinuation

For all antipsychotics, the British National Formulary recommends a gradual dose reduction when discontinuing 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 as a transient withdrawal symptom. It may also result in recurrence of the condition that is being treated. Rarely tardive dyskinesia can occur when the medication is stopped.

Pharmacology

Pharmacodynamics

Asenapine shows high affinity (pKi) for numerous receptors, including the serotonin 5-HT1A (8.6), 5-HT1B (8.4), 5-HT2A (10.2), 5-HT2B (9.8), 5-HT2C (10.5), 5-HT5A (8.8), 5-HT6 (9.5), and 5-HT7 (9.9) receptors, the adrenergic α1 (8.9), α2A (8.9), α2B (9.5), and α2C (8.9) receptors, the dopamine D1 (8.9), D2 (8.9), D3 (9.4), and D4 (9.0) receptors, and the histamine H1 (9.0) and H2 (8.2) receptors. It has much lower affinity (pKi < 5) for the muscarinic acetylcholine receptors. Asenapine behaves as a partial agonist at the 5-HT1A receptors. At all other targets asenapine is an antagonist.

Even relative to other atypical antipsychotics, asenapine has unusually high affinity for the 5-HT2A, 5-HT2C, 5-HT6, and 5-HT7 receptors, and very high affinity for the α2 and H1 receptors.

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

Who was Edward Bibring?

Introduction

Edward Bibring (1894–1959) was an Austrian American psychoanalyst. He studied philosophy and history at the University of Czernowitz until the First World War.

After his military service he went to study medicine at the University of Vienna, and later was accepted for training by the Vienna Psychoanalytic Society, in which he became an associate member from 1925, and then a full member in 1927. He was closely associated with Sigmund Freud. He was an co-editor of the Internationale Zeitschrift für Psychoanalyse for a brief period. In 1921 he married his fellow analyst Grete L. Bibring, and in 1941 the pair emigrated to the US.

Writings

His publishing’s focused on scientific contributions to the theory of psychoanalytic therapy, the study of depression, and the history of psychoanalysis.

Bibring’s early writings included studies of the instincts, and of the repetition compulsion. He also wrote a pair of articles on paranoia in schizophrenia, including a case study of a woman who believed herself to be persecuted by someone called “Behind”, a figure onto whom she had projected aspects of her own rear.

Ernest Jones reported with approval Bibring’s measured disagreement with Freud’s concept of the death drive:

“Instincts of life and death are not psychologically perceptible as such; they are biological instincts whose existence is required by hypothesis alone…[&] ought only to be adduced in a theoretical context and not in discussion of a clinical or empirical nature”.

While struggling with writer’s block in the States, Bibring did publish a 1954 article on the role of abreaction in what he called “emotional reliving” – a theme later developed by Vamik Volkan in his re-grief therapy.

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

Who was Edmund Bergler (1899-1962)?

Introduction

Edmund Bergler (20 July 1899 to 06 February 1962) was an Austrian-born American psychoanalyst whose books covered such topics as childhood development, mid-life crises, loveless marriages, gambling, self-defeating behaviours, and homosexuality. He has been described as the most important psychoanalytic theorist of homosexuality in the 1950s.

Biography

Edmund Bergler was born in Kolomyia, in today’s Ukraine, in 1899 into a Jewish family. Bergler fled Nazi Austria in 1937–1938 and settled in New York City, where he worked as a psychoanalyst. Bergler wrote 25 psychology books along with 273 articles that were published in leading professional journals. He also had unfinished manuscripts of dozens of more titles in the possession of the Edmund and Marianne Bergler Psychiatric Foundation. He has been referred to as “one of the few original minds among the followers of Freud“. Delos Smith, science editor of United Press International, said Bergler was “among the most prolific Freudian theoreticians after Freud himself”.

Work

Summarising his work, Bergler said that people were heavily defended against realization of the darkest aspects of human nature, meaning the individual’s emotional addiction to unresolved negative emotions. He wrote in 1958, “I can only reiterate my opinion that the superego is the real master of the personality, that psychic masochism constitutes the most dangerous countermeasure of the unconscious ego against the superego’s tyranny, that psychic masochism is ‘the life-blood of neurosis’ and is in fact the basic neurosis. I still subscribe to my dictum, ‘Man’s inhumanity to man is equaled only by man’s inhumanity to himself.'”

Sexuality

Bergler was the most important psychoanalytic theorist of homosexuality in the 1950s. According to Kenneth Lewes, a gay psychiatrist, “…Bergler frequently distanced himself from the central, psychoanalytical tradition, while at the same time claiming a position of importance within it. He thought of himself as a revolutionary who would transform the movement.” Near the end of his life, Bergler became an embarrassment to many other analysts: “His views at conferences and symposia were reported without remark, or they were softened and their offensive edge blunted.” However, it is unknown where did Lewes got this information, because there is no published autobiography of Bergler.

Bergler was highly critical of sex researcher Alfred C. Kinsey, and rejected the Kinsey scale, deeming it to be based on flawed assumptions. In an article published in the peer-reviewed medical journal Psychiatric Quarterly, Bergler criticized Alfred C. Kinsey: “Statistically speaking, Kinsey avoids with 100 percent completeness even the smallest concession to the existence of the dynamic unconscious. According to the “taxonomic approach,” to which Kinsey adheres, the “human animal,” as Kinsey calls homo sapiens, seems not yet to have developed the unconscious part of his personality…” “Derogatory remarks about Freudian psychoanalysis are mainly based on ignorance or resistance, or both. When this pair of characteristics occurs in biased laymen, one explains it away as typical resistance to acceptance of unconscious facts. The reason for this attitude in biased scientists is, of course, identical, though less defensible.” Bergler also states that: “Psychoanalytically, we know today that a complicated inner defence is involved. Homosexuals approve of their perversion because such acceptance of it – corresponding to a defence mechanism – enables them to hide unconsciously their deepest conflict, oral-masochistic regression. Since the homosexual who has not been treated has no inkling of the real state of affairs, he clings “proudly” to his defence mechanism. Only in cases in which a portion of inner guilt is not satiated by the real difficulties (hiding, social ostracism, extortion) which every homosexual experiences does the problem of changing come up.”

He is noted for his insistence on the universality of unconscious masochism. He is remembered for his theories about both homosexuality and writer’s block – a term he coined in 1947. Bergler, who did more work on the subject than any other psychoanalyst, argued that all gamblers gamble because of “psychic masochism”.

Legacy

Novelist Louis Auchincloss named his book The Injustice Collectors (1950) after Bergler’s description of the unconscious masochist of that type.

Bergler’s Homosexuality: Disease or Way of Life? (1956) was cited in Irving Bieber et al.’s Homosexuality: A Psychoanalytic Study of Male Homosexuals (1962). Bieber et al. mention Bergler briefly, noting that like Melanie Klein, he regarded the oral phase as the most determining factor in the development of homosexuality.

The philosopher Gilles Deleuze cited Bergler’s The Basic Neurosis (1949) in his Masochism: Coldness and Cruelty (1967), writing that, “Bergler’s general thesis is entirely sound: the specific element of masochism is the oral mother, the ideal of coldness, solicitude and death, between the uterine mother and the Oedipal mother.”

Arnold M. Cooper, former professor of psychiatry at Cornell University Medical College and a past president of the American Psychoanalytic Association, said of Bergler’s work: “I have adapted my model for understanding masochism from the work of Bergler, who regarded masochism as the basic neurosis from which all other neurotic behaviors derive. As long ago as 1949 . . . he felt, and I agree, [that the mechanism of orality] is paradigmatic for the masochistic character.”

Freud critic Max Scharnberg has given Bergler’s writings as an example of what he sees as the transparent absurdity of much psychoanalytic work in his The Non-Authentic Nature of Freud’s Observations (1993), writing that few present-day psychoanalysts would defend Bergler. Scharnberg disapprovingly notes Bergler’s claim that all homosexuals “are subservient when confronted with a stronger person, merciless when in power, unscrupulous about trampling on a weaker person.”

Bergler’s theories, with their assumption that the preservation of infantile megalomania or infantile omnipotence is of prime importance in the reduction of anxiety, have been seen as anticipating Heinz Kohut’s self psychology.

Psychotherapist Mike Bundrant has based much of his work on Bergler’s early theory of psychic masochism, although Bundrant has distanced himself from Bergler’s views on homosexuality, claiming Bergler was victim to his own prejudice in this area, or simply mistaken. Bundrant discusses inner masochism in the form of “psychological attachments” that fit consistent patterns over time.

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

Who was Donald Meltzer (1922-2004)?

Introduction

Donald Meltzer (1922–2004) was a Kleinian psychoanalyst whose teaching made him influential in many countries.

He became known for making clinical headway with difficult childhood conditions such as autism, and also for his theoretical innovations and developments. His focus on the role of emotionality and aesthetics in promoting mental health has led to his being considered a key figure in the “post-Kleinian” movement associated with the psychoanalytic theory of thinking created by Wilfred Bion.

Life and Work

Meltzer was born in New York City and studied medicine at Yale University. He practised in St. Louis as a psychiatrist, before moving to England in 1954 to have analysis with Melanie Klein. He joined the “Kleinian group”, became a teaching analyst of the British Psychoanalytical Society (BPS) and took on British citizenship. In the early 1980s disagreements about the mode of training led him to withdraw from the BPS. Meltzer worked with both adults and children. Initially his work with children was supervised by Esther Bick, who was creating a new and influential mode of psychoanalytic training at the Tavistock Clinic based on mother-child observation and following the theories of Melanie Klein. As a result of the regular travels and teaching of Meltzer and Martha Harris, his third wife, who was head of the Child Psychotherapy Training Course at the Tavistock Clinic, this model of psychoanalytic psychotherapy training became established in the principal Italian cities, in France and Argentina.

Meltzer taught for many years at the Tavistock Clinic, and practised privately in Oxford until his death. Owing to having left the BPS, his ideas remained controversial. He supervised psychoanalytically-oriented professionals in atelier-style groups throughout Europe, Scandinavia and South America, and his visits also included New York and California. Since his death in 2004 his reputation has increasingly regained ground also in his adoptive country. Several international congresses have focussed on his work: in London (1998), Florence (2000), Buenos Aires (2005), Savona (2005), Barcelona (2005) and Stavanger, Norway (2007).

Imago Group

Meltzer was a member of the Kleinian Imago Group founded by the Kleinian aesthete Adrian Stokes for discussing applied psychoanalysis. The group included among others Richard Wollheim, Wilfred Bion, Roger Money-Kyrle, Marion Milner and Ernst Gombrich. With Stokes he wrote a dialogue “Concerning the social basis of art”. Meltzer’s aesthetic interests, combined with the mother-baby model of early learning processes, led to seeing psychoanalysis itself as an art form. His later works describe the relationship between analyst and analysand as an aesthetic process of symbol-making. This has had an influence on the philosophical view of the relation between art and psychoanalysis.

Overview

Some of Meltzer’s significant and widely used developments of Kleinian object relations theory are as follows:

  • The aesthetic conflict, the foundation for normal development, based on the internal mother-baby relationship, was formulated in Meltzer and Harris Williams (1988) The Apprehension of Beauty
  • Intrusive identification, a form of projective identification associated with life in the Claustrum (narcissistic pathology), first formulated in early seminal papers “The relation of anal masturbation to projective identification” and “The delusion of clarity of insight”, and expanded in The Claustrum (1992)
  • Pseudo-maturity, a common clinical manifestation of arrested development
  • Adhesive identification and dismantling in two-dimensional autistic states, formulated in a work documenting Meltzer’s experience with 5 colleagues in treating autistic children, Explorations in Autism (1975)
  • The preformed transference, first described in The Psychoanalytical Process (1967), referring to the patient’s initial preconceptions about a psychoanalytic relationship which have to be overcome before a genuine transference and countertransference can be established
  • A reappraisal of Melanie Klein’s discovery of the combined internal object, which stresses its beneficial nature as a basis for mental development, begun in Richard Week-by-Week, Part II of The Kleinian Development (1978).

The Claustrum

In his final work, The Claustrum: An Investigation of claustrophobic phenomena (1988), Donald Meltzer developed a theory of claustrophobia. Meltzer offers a Kleinian/Bionian appreciation of the phenomenon of claustrophobia, arguing that the claustrum emerges as a failure of integration in early childhood development. If there occurs massive projective identification, that the child cannot sustain, its understanding both of its own corporeality, and that of others is severely impacted. It is a result of maternal failure in the reverie and leads to an incorrect construction of the internal mother. Claustrophobia in that sense “means to be imprisoned in a state of mind without getting out”, it has do with being trapped in the projective identification of others.

As a Teacher

Meltzer was well known internationally as a teacher and supervisor. He favoured an atelier-style system for the teaching and selection of candidates for psychoanalytical training, adumbrated in his paper, “Towards an atelier system”.

His method was to ask supervisees to present sessions of unedited clinical material, rather than finished papers. Several of his groups and individual supervisees have documented their experiences:

  • Castella, R., Farre, L., Tabbia, C. (2003) Supervisions with Donald Meltzer. London: Karnac.
  • Emanuel, R. (2004) “A personal tribute to Donald Meltzer”, Bulletin of the Association of Child Psychotherapists 149, 11–14
  • Fisher, J. (2000) “Reading Donald Meltzer: identification and intercourse as modes of reading and relating”, Exploring the Work of Donald Meltzer ed. Cohen and Hahn. London: Karnac, 188–202
  • Hoxter, S. (2000) “Experiences of learning with Donald Meltzer”, Exploring the Work of Donald Meltzered. Cohen and Hahn. London: Karnac,12–26
  • Psychoanalytic Group of Barcelona (2000), “A Learning Experience”, Exploring the Work of Donald Meltzer ed. Cohen and Hahn. London: Karnac, 203–14
  • Psychoanalytic Group of Barcelona (2002) Psychoanalytic Work with Children and Adults. London: Karnac
  • Psychoanalytic Group of Barcelona (2007) De un Teller psicoanalitico, a partir de Donald Meltzer. Barcelona: Grafein (in Spanish)
  • Oelsner, M. and Oelsner, R. (2005) “About supervision: an interview with Donald Meltzer”, British Journal of Psychotherapy, 21 (3).
  • Racker Group of Venice (2004) Transfert, Adolescenza, Disturbi del Pensiero. Armando (in Italian)

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

Who was David H. Malan (1922-2020)?

Introduction

David Huntingford Malan (21 March 1922 to 14 October 2020) was a British psychoanalytic psychotherapy practitioner and researcher recognised for his contribution to the development of psychotherapy.

He promoted scientific spirit of inquiry, openness, and simplicity within the field. He is also noted for his development of the Malan triangles, which became a rubric in which therapists can reflect upon what they are doing and where they are in relational space at any given moment.

Early Life

Malan was born in Ootacamund in the province of Tamil Nadu in India on 21 March 1922. His father was English, working in the Indian Civil service as Paymaster General of Madras State, and his mother Isabel (née Allen)was American. When Malan was seven years old his father died from pneumonia and Malan and his mother came to England. They moved into a house in Hartley Wintney which served as Malan’s home throughout his life. This early experience of grief was formative for his later work.

At preparatory boarding school Malan particularly enjoyed learning Latin and Greek, but as a scholar at Winchester he became interested in chemistry which he then studied, winning a scholarship to Balliol College, Oxford. He graduated in 1944 with a 1st class Honours degree in chemistry.

During the World War II, Malan was seconded to the Special Operations Executive (S.O.E), initially to develop devices for Resistance fighters, and later incendiary bombs for use in the Far East.

He was unable to partake in active service due to a foot injury. After the war he studied medicine at The London Hospital qualifying in 1952 and then trained in psychiatry at the Maudsley Hospital. Malan began his training in psychoanalysis whilst at Medical School. His initial analysis was with Michael Balint and then with Winnicott.

After a year at Courtaulds doing fundamental research, he knew he wanted to become a Psychotherapist.

Career

After qualifying from the London Hospital in 1952, he worked as a casualty officer, then as a psychiatrist at the Maudsley before transferring to the Tavistock Clinic in 1956. From 1956 to 1982, he remained at the Tavistock Clinic as a consultant psychiatrist, psychotherapist and psychoanalyst.

In 1956, at the Tavistock Clinic, Balint asked him to join his Brief Psychotherapy research group investigating whether brief focal therapy was effective. Malan analysed the results which were highly encouraging. During his early years as a psychotherapist, he already advocated the accurate, reproducible clinical descriptions, as well as the prediction of desirable outcomes prior to the process of therapy or an “intention to treat”, which are then followed by unbiased evaluation post-treatment. This approach was met with suspicion during the 1950s within the analytic community, including Malan’s colleagues at the Tavistock Clinic.

In 1967 Malan developed the Brief Psychotherapy workshop which all trainees were required to attend for one year and treat a patient under his supervision. It attracted students internationally as well as nationally. The aim was to achieve effective therapeutic results in the shortest possible time and to research the factors that made this happen.

The therapy was actively interpretive, using the elements of the Two Triangles – the Triangle of Conflict and the Triangle of Person – as the basis for many of the interventions that the therapists made.

The outcome data exploded the Myth of Superficiality whereby critics claimed that Brief Psychotherapy could only be helpful with superficially ill patients, that the technique used should be superficial and that only superficial improvements can be achieved.

At this time Malan lectured nationally and internationally many times in the US, Canada, Norway, Switzerland, Italy and Greece, describing his active interpretive approach and his investigation of the factors that made Brief Psychotherapy most effective. He received the highest medical Merit award for this work.

In 1974, Davanloo showed his tapes of Intensive Short-Term Dynamic Psychotherapy to Malan who was convinced by the evidence that the technique used was extremely effective. They began a twelve-year collaboration, doing workshops and lectures together with Davanloo showing his tapes of therapy and Malan outlining the concepts and explaining the principles of the technique.

In 1979, Malan wrote Individual Psychotherapy and the Science of Psychodynamics pub. Butterworth-Heinnemann which outlines the principles of Dynamic Psychotherapy from the most elementary to the most profound, using true case histories to illustrate each concept. It has been translated into 8 languages and following a second edition in 1995 is still in print as a classic textbook for psychotherapists.

Private Life

He was married to Muriel (née Still) from 1959 to about 1982, with whom he had a son called Peter. He later married Jennifer (Jennie) Ann (née Stead). He enjoyed travelling in the countryside with his wife Jennie including in Scotland, New Zealand and India.

Retirement and Death

After his retirement, Malan continued to write and lecture extensively on Brief Psychotherapy and Intensive Short Term Dynamic Therapy (ISTDP), publishing his last book “Lives Transformed”, in 2006, which he co-authored with Patricia Coughlin. He also put on Conferences in Oxford in 2006 and 2008 to demonstrate the effectiveness of ISTDP as a method of Brief Psychotherapy. Following these conferences, core training courses developed, and therapists, who completed them and have become experienced, have continued to lecture and teach subsequent core trainings.

In 2005, Malan received a Career Achievement Award in recognition of his contribution to Psychotherapy from the International Experiential Dynamic Therapy Association, of which he was Emeritus President since its inception. He died in 2020.

Brief Psychotherapy

Although trained as an analyst, initially using analysis in therapy, and recognising the validity of analytic insights, Malan has always been concerned that analysis takes too long and too few patients can be treated.

His research and writing therefore focussed on finding the most effective treatment that can help more patients in the shortest possible time.

Balint’s Brief Therapy Research Group

In 1956, after becoming a psychotherapist at the Tavistock Clinic, Malan was invited by Balint to join his Brief Psychotherapy research group investigating whether brief focal therapy was effective. Patients were treated using a radical interpretive approach and the results were evaluated against specified criteria and, in general, they were extremely good. Malan analysed the results in his Oxford DM thesis and subsequently developed the ideas in A Study of Brief Psychotherapy: Tavistock publications 1963. Other publications analysing aspects of the results were The Frontier of Brief Psychotherapy and Toward the Validation of Dynamic Psychotherapy – both published by Plenum in 1976.

Brief Psychotherapy Workshop

Following his appointment as a Consultant in the Adult dept., Malan introduced a Brief Psychotherapy workshop which all trainees were required to attend. They presented cases where they had used the principles of Brief Psychotherapy under his supervision. The aim was to achieve effective therapeutic results in the fewest sessions and to research the factors that made this possible.

In the workshop the technique was actively interpretive. The work was initially focussed on the presenting problems but became more wide-ranging with responsive patients and demonstrated deep and lasting changes.

An account of twenty-four therapies completed by trainees as part of the Brief Psychotherapy Workshop is summarised in ‘Psychodynamics, Training and Outcome’ by Malan and Osimo, pub. Butterworth –Heinemann 1992. It is based not only on the sessions but on the follow-up of a series of patients, and shows that good therapeutic results can be achieved by trainees under supervision.

The Two Triangles

A key element of therapy is the linking of the Two Triangles – the Triangle of Conflict (Defence, Anxiety and Hidden Feeling) and the Triangle of Persons (Current, Transference/Present and Past). The Triangle of Conflict illustrates the relation between anxiety, defences and the underlying impulses or feelings. The Triangle of Persons shows the links between the relationship with the therapist, with current people in the patient’s life, and with people from their past.

Malan always acknowledges that each Triangle was independently devised by Ezriel (1952) and Menninger (1958) respectively, but he showed how, when put together, the relation between them for the patient at any given moment in therapy, can form a reliable basis for many of the interventions that the therapist makes. Ref: Individual Psychotherapy and the Science of Psychodynamics (p. 80)

As early as 1963 in his analysis of cases in Balint’s workshop, Malan had identified that good outcome correlated with a high frequency of interpretations making a link between the transference and childhood, but the full significance and usefulness of the concept of linking the Triangles came later.

The Myth of Superficiality

Research from the workshop exploded the ‘myth of superficiality’ whereby critics maintain that Brief Psychotherapy is a superficial treatment that can only be effective with superficially ill patients, bringing about superficial results. Malan maintains that the aim of every session is to ‘put the patient in touch with as much of their true feelings as they can bear and that the long-term outcome should demonstrate deep and lasting changes.’ The work does not have to be focal and limited to specific problems and should lead to therapeutic changes that are wide-ranging, deep-seated and permanent. This has been shown in many of Malan’s follow-up studies where Brief Therapy and Intensive Short-term Dynamic Psychotherapy have been used.

Collaboration with Habib Davanloo

In 1974 Davanloo presented videotapes of his therapeutic work using Intensive Short-term Dynamic Psychotherapy (ISTDP) at the Tavistock Clinic. The essence of ISTDP is to enable the patient to reach and experience their hitherto buried, and often unconscious feelings, which have been governing their emotional responses leading to deep-seated neurotic patterns of behaviour that in many cases have crippled their lives. He does this by challenging the defences that the patient has been using to avoid painful feelings of loss, grief, anger, hate and guilt about people who they loved and /or needed when children.

Although aspects of Davanloo’s challenging and sometimes abrasive technique were antipathetic to him, Malan recognised that the challenge was to the defences, not to the patient directly, and results were conclusive and convincing. The videotapes showed undeniable evidence that patients could be treated in a relatively few sessions (40 or fewer) and fully recover from a range of longstanding emotional and psychosomatic illnesses.

Malan and Davanloo collaborated for twelve years from 1974, doing many Conferences and Workshops worldwide. Davanloo showed his tapes of therapy while Malan outlined the rationale and objectives of the technique and explained the elements of the therapy. After his retirement, Malan wrote many books and articles about Davanloo’s concepts and technique.

Subsequent Developments using Intensive Short-Term Dynamic Psychotherapy.

It became apparent that the abrasive element when challenging the defences is not necessary, and the same results can be achieved by blocking them much more gently but persistently until they disintegrate. Malan recognised that as long as the patient reaches and experiences the buried, often previously unconscious painful feelings, they no longer have the power to govern their emotional responses. It is the avoidance of these feelings that underlies many neurotic and psychosomatic symptoms.

Malan has worked with many of Davanloo’s ex-trainees lecturing and writing extensively. In 2006 he co-authored with Patricia Coughlin ‘Lives Transformed – a Revolutionary Method of Dynamic Psychotherapy’ pub. Karnac.

In order to introduce Intensive Short-term Dynamic Psychotherapy to the UK, Malan organised two Conferences in Oxford in 2006 and 2008, where video-tapes of therapies were shown. Following these Core Training groups were established. Subsequent Conferences have been held demonstrating ISTDP and currently there are Core trainings in London and the North of England. Malan hopes ISTDP will become available as a treatment method on the NHS as it so effective, but it is difficult to learn and challenging to do.

Scientific Principles and Brief Psychotherapy

A hallmark of Malan’s work is his scientific approach to research in Psychotherapy. He is convinced that psychodynamic processes can and should be scientifically studied, and he rigorously insists on long-term follow-ups to see how effective therapy really has been and what factors contributed to this.

Outcome Studies

Malan believes that one of the most important tools for this ‘objective study of subjective matter’ is long-term follow-up interviews to obtain reliable psychodynamic outcome data. He considers that questionnaires are useless, and proper follow-up interviews are necessary based on the initial criteria the therapist sets for the complete resolution of the presenting problems. To this end he has carried out many such follow-ups and trained others to do so. These outcome studies are actually process and outcome studies as they analyse the process of change as well as the long-term results. He published papers throughout his career evaluating outcome data which showed that the results of Brief Psychotherapy are as good as, or better than, those found in long-term therapy.

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/David_H._Malan >; 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.