Category: Mental Health Treatment

What is Fencamfamin?

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Introduction

Fencamfamin (INN), also known as fencamfamine or by the brand names Glucoenergan and Reactivan, is a stimulant which was developed by Merck in the 1960s.

Medical Uses

Fencamfamin is still used, though rarely, for treating depressive day-time fatigue, lack of concentration and lethargy, particularly in individuals who have chronic medical conditions, as its favourable safety profile makes it the most suitable drug in some cases.

Adverse Effects

Fencamfamin is well tolerated and causes minimal circulatory effects. Extended use may result in a dryness of the mouth.

Contraindications

Not to be used with heart diseases, angina pectoris and decompensated cardiac insufficiency, glaucoma, hyper-excitability and thyrotoxicosis or while treated with monoamine oxidase inhibitors.

Overdose

Symptoms of overdose are nausea, agitation and restlessness, dryness of the mouth, dizziness and tremor. In gross overdosage also associated with dyspnoea, tachycardia, disorientation and convulsions.

Research

In a study on slices of rat corpus striatum and substantia nigra fencamfamin acted as an indirect dopamine agonist. It released dopamine by a similar mechanism to amphetamines, but was ten times less potent than dexamphetamine at producing this effect. The main mechanism of action was instead inhibition of dopamine reuptake. Also unlike amphetamines, fencamfamin does not inhibit the action of monoamine oxidase enzymes. It was concluded that, at least in the models employed, the in vitro profile of fencamfamin is more similar to that of nomifensine, a reportedly pure uptake inhibitor, than to d-amphetamine.

In animal experiments on place preference fencamfamin produced a significant place preference only at the dose of 3.5 mg/kg. The experiments suggested a relation to dopamine D1 receptors, and also to opioid receptors in the reinforcement produced by fencamfamin, as place preference was blocked by the selective dopamine D1 antagonist SCH 23390 and by the opioid antagonist naloxone. A similar place preference, which was blocked by naloxone and by SCH 23390 and by raclopride, has been seen in a study on rats with drinking water. Animals treated with naloxone before the conditioning sessions showed a place aversion instead of the place preference found in saline-treated animals. Naloxone also reduced drinking. It was proposed that naloxone induced a state of frustrative nonreward. It was suggested that both dopamine and (endogenous) opioids are important for water-induced reinforcement. Possible interactions between these two neurotransmitter systems were discussed.

Synthesis

Fencamfamin may be synthesized in a straightforward fashion via the Diels-Alder reaction between cyclopentadiene and β-nitrostyrene (1-nitro-2-phenyl-ethene). The C=C double bond and the nitro-group in the resulting norcamphene derivative are then reduced to give the saturated norcamphane derivative. Finally, the amino-group is ethylated.

Although β-nitrostyrene is commercially available, it is also very easily prepared using the Henry Reaction between benzaldehyde and nitromethane.

The Diels-Alder reaction of β-nitrostyrene and cyclopentadiene is described in a number of early papers.

The reduction of the nitroalkene may be carried out sequentially. The alkene’s double bond is typically reduced using hydrogen and a transition metal catalyst like Ni or Pt, while the nitro group is reduced to the amine with a metal/acid combination, such as Fe/HCl. The reduction of both functional groups can also be achieved simultaneously by the use of Raney nickel, and this transformation has recently been optimized by Russian chemists.

Originally achieved under reductive amination conditions involving the reaction of the amine with acetaldehyde in the presence of Pt, ethylation of the amino-group has been improved by the use of Ra-Ni and ethanol.

The stereochemical consequences of the steps involved in the reaction sequence outlined above have been studied. Thus, the Diels-Alder cycloaddition leads to a product in which the nitro- and phenyl- groups are in a trans- relationship to each other. This product is actually a mixture of stereoisomers, in which the pair of enantiomers having the nitro- group in the endo- position and the phenyl- group in the exo- position predominates over the enantiomeric pair with exo-nitro and endo-phenyl groups. Although the isomeric composition of the Diels-Alder adduct itself does not seem to have been determined, Poos et al. reported a ratio of ~3:1 for the saturated un-ethylated amine derived from it. Novakov and co-workers, citing a thesis study, report that the corresponding ratio of endo-N-ethyl/exo-Φ : exo-N-ethyl/endo-Φ enantiomeric pairs is ~9:1 in fencamfamin itself.

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What is Ethylphenidate?

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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?

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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?

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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?

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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.

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What is Brexpiprazole?

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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.

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What is Asenapine?

Published on by Andrew Marshall1 Comment

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.

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What is Milieu Therapy?

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Introduction

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

Outline

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

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

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

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

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What is the International Expressive Arts Therapy Association?

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Introduction

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

Outline

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

It provides:

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

Memberships

IEATA offers two kinds of registration for professional memberships.

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

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What is the Cognitive Behavioural Analysis System of Psychotherapy?

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Introduction

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

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

Basic Assumptions

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

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

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

Treatment Strategies

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

Therapist Role

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

Outcome Goals of Treatment and Beyond

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

Combination Treatment

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

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

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

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

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