Tag: Depression

What is Phenylpiracetam?

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Introduction

Phenylpiracetam, also known as fonturacetam (INNTooltip International nonproprietary name) and sold under the brand names Phenotropil, Actitropil, and Carphedon among others, is a stimulant and nootropic medication used in Russia and certain other Eastern European countries in the treatment of cerebrovascular deficiency, depression, apathy, and attention, and memory problems, among other indications. It is also used in Russian cosmonauts to improve physical, mental, and cognitive abilities. The drug is taken by mouth.

Side effects of phenylpiracetam include sleep disturbances among others. The mechanism of action of phenylpiracetam was originally unknown. However, it was discovered that (R)-phenylpiracetam is a selective atypical dopamine reuptake inhibitor in 2014. In addition, phenylpiracetam interacts with certain nicotinic acetylcholine receptors. Chemically, phenylpiracetam is a racetam and phenethylamine and is structurally related to piracetam.

Phenylpiracetam was first described by 1983. It was approved for medical use in Russia in 2003. Development of (R)-phenylpiracetam (code name MRZ-9547) in the West as a potential treatment for fatigue related to Parkinson’s disease began by 2014.

Brief History

Phenylpiracetam was first described in the scientific literature by 1983. It was developed in 1983 as a medication for Soviet cosmonauts to treat the prolonged stresses of working in space. Phenylpiracetam was created at the Russian Academy of Sciences Institute of Biomedical Problems in an effort led by psychopharmacologist Valentina Ivanovna Akhapkina (Валентина Ивановна Ахапкина). Subsequently, it became available as a prescription drug in Russia. It was approved in 2003 for treatment of various conditions.

Pilot-cosmonaut Aleksandr Serebrov described being issued and using phenylpiracetam, as well as it being included in the Soyuz spacecraft’s standard emergency medical kit, during his 197-days working in space aboard the Mir space station. He reported:

“the drug acts as the equalizer of the whole organism, “tidying it up”, completely excluding impulsiveness and irritability inevitable in the stressful conditions of space flight.”

Medical Uses

Phenylpiracetam is used in the treatment of a variety of different medical conditions. It is specifically approved in Russia for treatment of cerebrovascular deficiency, depression, apathy, attention deficits, and memory decline. It is used to improve symptoms following encephalopathy, brain injury, and glioma surgery. The drug has been reported to improve symptoms of depression, anxiety, asthenia, and fatigue, as well as to improve cognitive performance and memory. It also has anticonvulsant effects and has been used as an add-on therapy in epilepsy.

Phenylpiracetam is typically prescribed as a general stimulant or to increase tolerance to extreme temperatures and stress.

Clinical use of phenylpiracetam has shown to be more potent than piracetam and is used for a wider-range of indications.

A few small clinical studies have shown possible links between prescription of phenylpiracetam and improvement in a number of encephalopathic conditions, including lesions of cerebral blood pathways, traumatic brain injury and certain types of glioma.

Clinical trials were conducted at the Serbsky State Scientific Centre for Social and Forensic Psychiatry. The Serbsky Centre, Moscow Institute of Psychiatry, and Russian Centre of Vegetative Pathology are reported to have confirmed the effectiveness of phenylpiracetam describing the following effects: improvement of regional blood flow in ischemic regions of the brain, reduction of depressive and anxiety disorders, increase the resistance of brain tissue to hypoxia and toxic effects, improving concentration and mental activity, a psycho-activating effect, increase in the threshold of pain sensitivity, improvement in the quality of sleep, and an anticonvulsant action, though with the side effect of an anorexic effect in extended use.

Available Forms

Phenylpiracetam is available in the form of 100 mg oral tablets.

Contraindications

Phenylpiracetam has a number of contraindications, such as individual intolerance.

Side Effects

Side effects of phenylpiracetam include insomnia or sleep disturbances, psychomotor agitation, flushing, a feeling of warmth, and increased blood pressure, among others.

Overdoses

Overdose has not been reported.

Pharmacology

Pharmacodynamics

Phenylpiracetam is a racetam and is described as a stimulant. Racetams have a variety of different pharmacological activities and have varying effects. For example, phenylpiracetam is a stimulant, piracetam is a nootropic, and levetiracetam is an anticonvulsant. The mechanisms of action of most racetams, with some exceptions, are unknown.

Phenylpiracetam is a racemic mixture.4-Phenylpiracetam is the most active enantiomer and is much more potent in stimulating locomotor activity than (S)-phenylpiracetam, which is ineffective. However, (S)-phenylpiracetam retains some activity in most pharmacological tests. On the other hand, in one animal test, the passive avoidance test, (S)-phenylpiracetam appeared to be antagonistic of (R)-phenylpiracetam.

Dopamine Reuptake Inhibitor

Experiments performed on Sprague-Dawley rats in a European patent for using phenylpiracetam to treat sleep disorders showed an increase in extracellular dopamine levels after administration. The patent asserts discovery of phenylpiracetam’s action as a dopamine reuptake inhibitor as its basis.

The peculiarity of this invention compared to former treatment approaches for treating sleep disorders is the so far unknown therapeutic efficacy of (R)-phenylpiracetam, which is presumably based at least in part on the newly identified activity of (R)-phenylpiracetam as the dopamine re-uptake inhibitor

Both enantiomers of phenylpiracetam, (R)-phenylpiracetam and (S)-phenylpiracetam, have been described in peer-reviewed research as dopamine transporter (DAT) inhibitors in rodents, confirming the patent claim. Their actions at the norepinephrine transporter (NET) vary: (R)-phenylpiracetam acts as a dual norepinephrine–dopamine reuptake inhibitor (NDRI), with 11-fold lower affinity for the NET than for the DAT, whereas the (S)-enantiomer is selective for the DAT. However, whereas (R)-phenylpiracetam stimulates locomotor activity, (S)-phenylpiracetam does not do so. This variation in effects has also been seen with other dopamine reuptake inhibitors.

Other atypical dopamine reuptake inhibitors include modafinil, mesocarb (Sydnocarb), and solriamfetol.

Other Actions

Phenylpiracetam binds to α4β2 nicotinic acetylcholine receptors in the mouse brain cortex with an IC50Tooltip half-maximal inhibitory concentration of 5.86 μM.

Racetams generally, but including phenylpiracetam, have been described as AMPA receptor potentiators.

Animal Studies

Research on animals has indicated that phenylpiracetam may have anti-amnesic, antidepressant, anxiolytic, and anticonvulsant effects.

Phenylpiracetam has been shown to reverse the sedative or depressant effects of the benzodiazepine diazepam, increases operant behaviour, inhibits post-rotational nystagmus, prevents retrograde amnesia, and has anticonvulsant properties in animal models.

In Wistar rats with gravitational cerebral ischemia, phenylpiracetam reduced the extent of neuralgic deficiency manifestations, retained the locomotor, research, and memory functions, increased the survival rate, and lead to the favouring of local cerebral flow restoration upon the occlusion of carotid arteries to a greater extent than did piracetam.

In tests against a control, Sprague-Dawley rats given free access to less-preferred rat chow and trained to operate a lever repeatedly to obtain preferred rat chow performed additional work when given methylphenidate, dextroamphetamine, and phenylpiracetam. Rats administered 100 mg/kg phenylpiracetam performed, on average, 375% more work than rats given placebo, and consumed little non-preferred rat chow. In comparison, rats administered 1mg/kg dextroamphetamine or 10 mg/kg methylphenidate performed, on average, 150% and 170% more work respectively, and consumed half as much non-preferred rat chow.

Present data show that (R)-phenylpiracetam increases motivation, i.e. the work load, which animals are willing to perform to obtain more rewarding food. At the same time consumption of freely available normal food does not increase. Generally this indicates that (R)-phenylpiracetam increase motivation […] The effect of (R)-phenylpiracetam is much stronger than that of methylphenidate and amphetamine.

Pharmacokinetics

The pharmacokinetics of phenylpiracetam in humans are unpublished. In any case, the drug is described as having an oral bioavailability of approximately 100%, as having an onset of action of less than 1 hour, as not being metasbolised, as being excreted unchanged about 40% in urine and 60% in bile and sweat, and as having an elimination half-life of 3 to 5 hours. In rodents, its absorption occurs within 1 hour with oral administration or intramuscular injection and its elimination half-life is 2.5 to 3 hours.

Chemistry

Phenylpiracetam, also known as 4-phenylpiracetam, is a racetam (i.e. a 2-oxo-1-pyrrolidine acetamide derivative) and the 4-phenyl-substituted analogue of piracetam. In contrast to piracetam and most other racetams however, phenylpiracetam contains β-phenylethylamine within its chemical structure and hence can additionally be conceptualised as a substituted phenethylamine.

Phenylpiracetam is a racemic mixture of (R)- and (S)-enantiomers, (R)-phenylpiracetam (MRZ-9547) and (S)-phenylpiracetam.

Derivatives

RGPU-95 (4-chlorophenylpiracetam) is a derivative of phenylpiracetam described as having 5- to 10-fold greater potency. Cebaracetam (CGS-25248; ZY-15119) is a derivative of RGPU-95 in which the terminal amide has been replaced with a 2-piperazinone moiety.

Methylphenylpiracetam, including all four of its stereoisomers (especially the (4R,5S)-enantiomer E1R), is a positive allosteric modulator of the sigma σ1 receptor. It is currently the only known racetam demonstrating σ1 receptor modulation. Whereas phenylpiracetam stimulates locomotor activity in animals, the E1R enantiomer of methylphenylpiracetam does not do so at doses of up to 200 mg/kg.

Phenylpiracetam hydrazide is a hydrazide derivative of phenylpiracetam described as having anticonvulsant effects.

Other derivatives of phenylpiracetam have also been developed and studied.

Society and Culture

Availability

While not prescribed as a pharmaceutical in the West, in Russia and certain other Eastern European countries it is available as a prescription medicine under brand names including Phenotropil (also spelled Fenotropil, Phenotropyl, and Fenotropyl), Actitropil, and Nanotropil, among others.

Phenylpiracetam is not scheduled by the United States Drug Enforcement Administration (DEA) as of 2016.

Manufacturer

Phenylpiracetam is manufactured by the pharmaceutical companies Valenta Pharm and Pharmstandard (Pharmstandart) in Russia.

Doping in Sport

Phenylpiracetam has stimulant effects and may be used as a doping agent in sport. As a result, it is on the list of stimulants banned for in-competition use by the World Anti-Doping Agency (WADA). This list is applicable in all Olympic sports. Owing to its unique stimulant properties among racetams, phenylpiracetam is the only racetam on the WADA prohibited list.

Research

Phenylpiracetam has been studied in the treatment of stroke and glaucoma.

The more active enantiomer of phenylpiracetam, (R)-phenylpiracetam, was under development for fatigue related to Parkinson’s disease. However, no recent development has been reported. There was also interest in the compound for fatigue related to depression and other conditions, but this was not pursued. 6-Phenylpiracetam has been identified as a selective atypical dopamine reuptake inhibitor (DRIs), and similarly to other DRIs, shows pro-motivational effects in animals and reverses motivational deficits.

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

New Scientist Articles: Sleeping Pills & Myths and Mental Illness

Published on by Andrew MarshallLeave a comment

Introduction

I have attached two articles from the New Scientist’s 18 January 2025 magazine discussing:

  • A news article about how sleeping pills can disrupt the brain by Grace Wade.
  • A book review (titled Myths and Mental Illness) by David Robinson of Chemically Imbalanced by author Joanna Moncrieff.

I think you will agree that both make interesting reading.

Mag – New Scientist (2025-01-18), Page 20Download
Mag – New Scientist (2025-01-18), Page 30Download

What was STAR*D?

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Introduction

Sequenced Treatment Alternatives to Relieve Depression (STARD) was a collaborative study on the treatment of depression, funded by the National Institute of Mental Health. Its main focus was on the treatment of depression in patients where the first prescribed antidepressant proved inadequate. A key feature of the study was its aim to be more generalisable to real clinical situations; this was done through the use of minimal exclusion criteria, incorporating patient preference, and not blinding the treatments (i.e. the patient and clinician both knew what treatment the patient was receiving).

The STARD trial included remission (the near-absence of symptoms, rather than simply a reduction in symptoms) as an outcome measure, as there is evidence that patients with depression who achieve remission function better and are less prone to relapse than those who achieve only partial improvement in symptoms.

This report had profound impact on the promotion of antidepressants but later accused of having been subjected to multiple levels of fraud.

Trial

The STAR*D trial enrolled 4,041 outpatients with nonpsychotic depression at 23 psychiatric and 18 primary care sites. The trial was completed in 2006, and data from it has been available since 2008.

The trial involved four different treatment levels, and patients were encouraged to enter the next level of treatment if they failed to achieve remission or response (50% reduction in symptoms) after a specified number of weeks.

In level one, patients received the selective serotonin reuptake inhibitor (SSRI) citalopram for up to 14 weeks, with adjustment of the dose being managed by their own physicians. If patients achieved remission or response during that time period, they could enter a 12-month naturalistic follow-up, during which time the researchers did not have any influence over the treatment plan. Non-remitters were encouraged to enter level two.

In level two, there were seven different treatment options, and cognitive behavioural therapy (CBT) was included as the psychotherapy option. There were three combination options (either an antidepressant or CBT added to citalopram), and four switch options (to either a different antidepressant or CBT). Those who remitted or responded were offered 12-month naturalistic follow-up; non-remitters after two medication trials were encouraged to enter level 3; other non-remitters entered level 2A, which involved a second antidepressant trial.

In level three, patients were offered the addition of lithium or triiodothyronine (a thyroid hormone) to their antidepressant, or a switch to another antidepressant (mirtazapine or nortriptyline). This continued for 12 weeks.

Level four consisted of the monoamine oxidase inhibitor tranylcypromine or a combination of venlafaxine and mirtazapine.

Results

For level one, the remission rate was 28-33% (depending on the symptom scale used), and the response rate was 47%. Higher remission rates were seen in patients who were Caucasian, female, employed, or had higher levels of income or education. Lower remission rates were seen in those with longer depressive episodes, co-occurring anxiety or substance use disorders, and more physical illness.

For level two, patients who received CBT, either alone or combined with citalopram, had similar response and remission rates compared to those who were receiving medication(s) only; however, for those patients who remained on citalopram, those who had another antidepressant added achieved remission more rapidly than those who had CBT added. Among the patients who were switched to a different antidepressant, there was no significant difference among the different antidepressants.

For level three, the remission rates based on the HAM-D symptom scale were 12.3% for mirtazapine and 19.8% for nortriptyline, although the difference was not large enough for statistical significance. The remission rates based on the HAM-D in the combination strategy were 15.9% for lithium and 24.7% for triiodothyronine, but the difference was not statistically significant. However, more patients receiving lithium than triiodothyronine left the study due to side effects.

For level four, the average remission rate was 13%, with no statistically significant difference between tranylcypromine and the venlafaxine/mirtazapine combination. More patients receiving tranylcypromine left the study due to side effects.

Overall, the study findings indicate that patients who do not achieve remission or response after several weeks of citalopram treatment could achieve those outcomes by the end of 14 weeks. The STAR*D researchers state that their data “suggest that a patient with persistent depression can get well after trying several treatment strategies, but his or her odds of beating the depression diminish as additional treatment strategies are needed.” With failed treatment at a higher step, the chances of remission were smaller – and this decrease was particularly significant after level two. For those who did achieve full remission, there was a decreased chance of relapse at 12-month (naturalistic) follow-up compared to those patients who only responded.

A reanalysis published in 2023 concluded that STAR*D’s cumulative remission rate was approximately half of that reported.

Criticism

Criticism of bias has been raised by certain researchers about the STAR*D trial:

  • The research contract provided for the assessment of depression by the HRSD and IDS-C30 scales. Instead, depression was assessed using an ex-nihilo study scale (QIDS-SR), which was used for both medical decision-making and scientific evaluation.
  • STAR*D changed the inclusion and exclusion criteria for subjects during the study, so 931 subjects were included when they met the exclusion criteria, and 370 subjects were excluded while they met the inclusion criteria. These changes resulted in an increase in the average score of the subjects: according to the inclusion and exclusion criteria provided by the original protocol, the remission rate was 38%; according to the inclusion and exclusion criteria implemented retrospectively, the remission rate is 67%.
  • Only 7% of subjects in remission remained stable and stayed in the study until the end. This represents only 3% of subjects according to the original inclusion and exclusion criteria (108 out of 3,671). This has not been specified.

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What is Nortiptyline?

Published on by Andrew Marshall1 Comment

Introduction

Nortriptyline, sold under the brand name Aventyl, among others, is a tricyclic antidepressant (TCA). This medicine is also sometimes used for neuropathic pain, attention deficit hyperactivity disorder (ADHD), smoking cessation and anxiety. Its use for young people with depression and other psychiatric disorders may be limited due to increased suicidality in the 18–24 population initiating treatment. Nortriptyline is not a preferred treatment for ADHD or smoking cessation. It is taken by mouth.

Common side effects include dry mouth, constipation, blurry vision, sleepiness, low blood pressure with standing, and weakness. Serious side effects may include seizures, an increased risk of suicide in those less than 25 years of age, urinary retention, glaucoma, mania, and a number of heart issues. Nortriptyline may cause problems if taken during pregnancy. Use during breastfeeding appears to be relatively safe. It is a TCA and is believed to work by altering levels of serotonin and norepinephrine.

Nortriptyline was approved for medical use in the US in 1964. It is available as a generic medication. In 2022, it was the 191st most commonly prescribed medication in the US, with more than 2 million prescriptions.

Brief History

Nortriptyline was developed by Geigy. It first appeared in the literature in 1962 and was patented the same year. The drug was first introduced for the treatment of depression in 1963.

Medical Uses

Nortriptyline is used to treat depression. A level between 50 and 150 ng/mL of nortriptyline in the blood generally corresponds with an antidepressant effect.

It is also used off-label for the treatment of panic disorder, ADHD, irritable bowel syndrome, tobacco-cessation, migraine prophylaxis and chronic pain or neuralgia modification, particularly temporomandibular joint disorder.

Irritable Bowel Syndrome

Nortriptyline has also been used as an off-label treatment for irritable bowel syndrome (IBS).

Contraindications

Nortriptyline should not be used in the acute recovery phase after myocardial infarction (heart attack). Use of TCAs along with a monoamine oxidase inhibitor (MAOI), linezolid, or IV methylene blue are contraindicated as it can cause an increased risk of developing serotonin syndrome.

Closer monitoring is required for those with a history of cardiovascular disease, stroke, glaucoma, or seizures, as well as in persons with hyperthyroidism or receiving thyroid hormones.

Side Effects

The most common side effects include dry mouth, sedation, constipation, increased appetite, blurred vision and tinnitus. An occasional side effect is a rapid or irregular heartbeat. Alcohol may exacerbate some of its side effects.

Overdose

Refer to Tricyclic Antidepressant Overdose.

The symptoms and the treatment of an overdose are generally the same as for the other TCAs, including anticholinergic effects, serotonin syndrome and adverse cardiac effects. TCAs, particularly nortriptyline, have a relatively narrow therapeutic index, which increase the chance of an overdose (both accidental and intentional). Symptoms of overdose include: irregular heartbeat, seizures, coma, confusion, hallucination, widened pupils, drowsiness, agitation, fever, low body temperature, stiff muscles and vomiting.

Interactions

Excessive consumption of alcohol in combination with nortriptyline therapy may have a potentiating effect, which may lead to the danger of increased suicidal attempts or overdosage, especially in patients with histories of emotional disturbances or suicidal ideation.

It may interact with the following drugs:

  • Heart rhythm medications such as flecainide (Tambocor), propafenone (Rhythmol), or quinidine (Cardioquin, Quinidex, Quinaglute)
  • Cimetidine
  • Guanethidine
  • Reserpine

Pharmacology

Nortriptyline is a strong norepinephrine reuptake inhibitor and a moderate serotonin reuptake inhibitor. Additionally, nortriptyline inhibits the activity of histamine and acetylcholine.

Pharmacodynamics

Nortriptyline is an active metabolite of amitriptyline by demethylation in the liver. Chemically, it is a secondary amine dibenzocycloheptene and pharmacologically it is classed as a first-generation antidepressant.

Nortriptyline may also have a sleep-improving effect due to antagonism of the H1 and 5-HT2A receptors. In the short term, however, nortriptyline may disturb sleep due to its activating effect.

In one study, nortriptyline had the highest affinity for the dopamine transporter among the TCAs (KD = 1,140 nM) besides amineptine (a norepinephrine–dopamine reuptake inhibitor), although its affinity for this transporter was still 261- and 63-fold lower than for the norepinephrine and serotonin transporters (KD = 4.37 and 18 nM, respectively).

Pharmacogenetics

Nortriptyline is metabolised in the liver by the hepatic enzyme CYP2D6, and genetic variations within the gene coding for this enzyme can affect its metabolism, leading to changes in the concentrations of the drug in the body. Increased concentrations of nortriptyline may increase the risk for side effects, including anticholinergic and nervous system adverse effects, while decreased concentrations may reduce the drug’s efficacy.

Individuals can be categorised into different types of CYP2D6 metabolisers depending on which genetic variations they carry. These metaboliser types include poor, intermediate, extensive, and ultrarapid metabolisers. Most individuals (about 77–92%) are extensive metabolisers, and have “normal” metabolism of nortriptyline. Poor and intermediate metabolisers have reduced metabolism of the drug as compared to extensive metabolisers; patients with these metaboliser types may have an increased probability of experiencing side effects. Ultrarapid metabolisers use nortriptyline much faster than extensive metabolisers; patients with this metaboliser type may have a greater chance of experiencing pharmacological failure.

The Clinical Pharmacogenetics Implementation Consortium recommends avoiding nortriptyline in persons who are CYP2D6 ultrarapid or poor metabolisers, due to the risk of a lack of efficacy and side effects, respectively. A reduction in starting dose is recommended for patients who are CYP2D6 intermediate metabolisers. If use of nortriptyline is warranted, therapeutic drug monitoring is recommended to guide dose adjustments. The Dutch Pharmacogenetics Working Group recommends reducing the dose of nortriptyline in CYP2D6 poor or intermediate metabolisers, and selecting an alternative drug or increasing the dose in ultrarapid metabolisers.

Chemistry

Nortriptyline is a tricyclic compound, specifically a dibenzocycloheptadiene, and possesses three rings fused together with a side chain attached in its chemical structure. Other dibenzocycloheptadiene tricyclic antidepressants include amitriptyline (N-methylnortriptyline), protriptyline, and butriptyline. Nortriptyline is a secondary amine tricyclic antidepressant, with its N-methylated parent amitriptyline being a tertiary amine. Other secondary amine tricyclic antidepressants include desipramine and protriptyline. The chemical name of nortriptyline is 3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-N-methyl-1-propanamine and its free base form has a chemical formula of C19H21N1 with a molecular weight of 263.384 g/mol. The drug is used commercially mostly as the hydrochloride salt; the free base form is used rarely. The CAS Registry Number of the free base is 72-69-5 and of the hydrochloride is 894-71-3.

Society and Culture

Generic Names

Nortriptyline is the generic name of the drug and its INNTooltip International Nonproprietary Name, BANTooltip British Approved Name, and DCFTooltip Dénomination Commune Française, while nortriptyline hydrochloride is its USANTooltip United States Adopted Name, USPTooltip United States Pharmacopeia, BANMTooltip British Approved Name, and JANTooltip Japanese Accepted Name. Its generic name in Spanish and Italian and its DCITTooltip Denominazione Comune Italiana are nortriptilina, in German is nortriptylin, and in Latin is nortriptylinum.

Brand Names

Brand names of nortriptyline include Allegron, Aventyl, Noritren, Norpress, Nortrilen, Norventyl, Norzepine, Pamelor, and Sensival, among many others.

Research

Although not approved by the US Food and Drug Administration (FDA) for neuropathic pain, randomised controlled trials have demonstrated the effectiveness of TCAs for the treatment of this condition in both depressed and non-depressed individuals. In 2010, an evidence-based guideline sponsored by the International Association for the Study of Pain recommended nortriptyline as a first-line medication for neuropathic pain. However, in a 2015 Cochrane systematic review the authors did not recommend nortriptyline as a first-line agent for neuropathic pain.

It may be effective in the treatment of tobacco-cessation.

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

Published on by Andrew Marshall1 Comment

Introduction

Brofaromine (proposed brand name Consonar) is a reversible inhibitor of monoamine oxidase A (RIMA) discovered by Ciba-Geigy. The compound was primarily researched in the treatment of depression and anxiety but its development was dropped before it was brought to market.

Brofaromine also acts as a serotonin reuptake inhibitor, and its dual pharmacologic effects offered promise in the treatment of a wide spectrum of depressed patients while producing less severe anticholinergic side effects in comparison with older standard drugs like certain of the tricyclic antidepressants.

Pharmacology

Brofaromine is a reversible inhibitor of monoamine oxidase A (RIMA, a type of monoamine oxidase inhibitor (MAOI)) and acts on epinephrine (adrenaline), norepinephrine (noradrenaline), serotonin, and dopamine. Unlike standard MAOIs, possible side effects do not include cardiovascular complications (hypertension) with encephalopathy, liver toxicity or hyperthermia.

Refer to Moclobemide.

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

Published on by Andrew Marshall1 Comment

Introduction

Moclobemide, sold under the brand names Amira, Aurorix, Clobemix, Depnil and Manerix among others, is a reversible inhibitor of monoamine oxidase A (RIMA) drug primarily used to treat depression and social anxiety. It is not approved for use in the United States, but is approved in other Western countries such as Canada, the UK and Australia. It is produced by affiliates of the Hoffmann–La Roche pharmaceutical company. Initially, Aurorix was also marketed by Roche in South Africa, but was withdrawn after its patent rights expired and Cipla Medpro’s Depnil and Pharma Dynamic’s Clorix became available at half the cost.

No significant rise in blood pressure occurs when moclobemide is combined with amines such as tyramine-containing foods or pressor amine drugs, unlike with the older irreversible and non-selective monoamine oxidase inhibitors (MAOIs), which cause a severe rise in blood pressure with such combination. Due to the lack of anticholinergic, cardiovascular, cognitive and psychomotor impairments moclobemide is advantageous in the elderly as well as those with cardiovascular disease.

Moclobemide was first introduced for medical use in 1989.

Refer to Brofaromine.

Brief History

Irreversible MAOI antidepressants were discovered accidentally in the 1950s but their popularity declined as their toxicity especially their dangerous food interactions became apparent and rival tricyclic antidepressants were discovered. Reversible MAOIs were developed in the hope that they would exert efficacy in depressive disorders but with less of the toxicity of the older irreversible compounds; moclobemide’s discovery and marketing brought the renewed interest in MAOIs due to an absence of dangerous tyramine food interactions and potent antidepressant effects. In 1992 moclobemide was launched onto the world markets. Moclobemide was the first reversible MAO-A inhibitor to be widely marketed. Moclobemide as well as other newer antidepressants such as the SSRIs led to changes in prescribing patterns and broadened the treatment options for the management of depressive disorders.

When moclobemide was discovered in 1972 in Switzerland, it was first hypothesized as being an antilipaemic or antibiotic, but the screenings were negative. The search for its antidepressant qualities, based on anticholinergic tests, also proved negative and moclobemide was then suspected of being an antipsychotic before its specific and reversible MAO-A inhibition qualities were detected. After the establishment of its lack of relevant interference with tyramine pressure response, clinical trials were launched in 1977 and further trials confirmed the broad antidepressant activity of RIMAs. It was first approved in Sweden in 1989 and then the United Kingdom and Europe as the first reversible and selective inhibitor of MAO-A and is now approved in over 50 countries worldwide. Subsequent research found that moclobemide is well tolerated in elderly patients and far superior to tricyclic antidepressants in terms of side effects, tolerability and overdose. With regard to effectiveness in the treatment of depression, moclobemide was determined to be as effective as all major antidepressant drug classes. There is no need for dietary restrictions in contrast to people on irreversible MAOIs and apart from an important interaction with other serotonergic enhancing agents such as SSRIs and pethidine, there are few serious drug interactions and because of these benefits, moclobemide became regarded as a beneficial addition to medical ‘prescribing arsenal’. Additionally moclobemide was found, unlike most other antidepressants on the market, to actually improve all aspects of sexual function. It is the only reversible MAOI in use in clinical practice. The fact that moclobemide’s pharmacokinetic properties are unaltered by age, that cognition is improved in the elderly, and moclobemide has low potential for food and drug interactions opened up a new avenue for the treatment of major depressive disorder. Due to a lack of financial incentive, such as the costs of conducting the necessary trials to gain approval, moclobemide is unavailable in the USA pharmaceutical market. In 2016 moclobemide was discontinued in Brazil for commercial reasons.

Medical Uses

Reversible selective MAOIs such as moclobemide are under-prescribed due to the misconception that the side effect profiles are analogous to that of the irreversible and non-selective MAOIs. MAOIs such as moclobemide are reported to have a relatively fast onset of action compared to other antidepressant drug classes, and have good long-term tolerability in terms of side effects.

Tolerance does not seem to occur; research has found that moclobemide retains its beneficial therapeutic properties in depression for at least a year.

  • Unipolar depression: Moclobemide has demonstrated effectiveness and efficacy in the treatment and management of major depressive disorder, with both endogenous and non-endogenous depression responding; in addition moclobemide has a fast onset of action compared to other antidepressants and is significantly more tolerable than the tricyclic antidepressants. Due to a good safety profile and low incidence of side effects moclobemide is likely to have a high level of acceptability by individuals suffering from depression. Higher doses (>450 mg/day) may be more effective in severe depression, while patients treated with a lower dose tend to respond less well than those treated with tricyclic antidepressants.
  • Psychotic depression, unipolar endogenous depression, melancholic depression, retarded depression, agitated depression and neurotic depression all respond to moclobemide, as does atypical depression. Unipolar endogenous depression is reported to have the best response to moclobemide therapy. Individuals suffering from depression who are given moclobemide are twice as likely to improve on moclobemide than on placebo. A concern of antidepressant adverse effects is sexual dysfunction; however, moclobemide has been found to actually increase libido and improve impaired erection, ejaculation and orgasm. Cardiovascular toxicity is a concern with antidepressants such as tricyclic antidepressants as well as the irreversible MAOIs; when cardiovascular toxicity is a concern, SSRIs or the reversible MAOIs such as moclobemide are an option as they lack or have a significantly reduced level of cardiovascular toxicity in terms of adverse effect as well as in overdose.
  • The effectiveness of moclobemide in agitated depression is equivalent to that of imipramine and sedative antidepressants such as amitriptyline, mianserin and maprotiline. The therapeutic response in agitated depressive individuals is similar to that seen in non-agitated depression; however, a past history of use of antidepressants reduces the chance of successful therapeutic response. The addition of a benzodiazepine to moclobemide therapy has not been found to be of benefit in this population group. Moclobemide has better tolerability compared to TCAs.
  • Dysthymia: moclobemide has been found to be effective in the treatment and management of this depressive disorder.
  • Social phobia: Moclobemide has been found to be effective for the treatment of social anxiety disorder in both short and long-term placebo controlled clinical trials. Moclobemide is effective but not as effective as the irreversible MAOIs in the treatment of social phobia. Maximal benefits can take 8–12 weeks to manifest. There is a high risk of treatment failure if there is co-morbid alcohol use disorder, however. The Australian Medicines Handbook lists social phobia as an accepted but not a licensed indication. The use of moclobemide in the treatment of social anxiety disorder has given mixed results with a tendency of response at higher doses (>300 mg/d) compared with placebo.
  • Smoking cessation: Moclobemide has been tested in heavy dependent smokers against placebo based on the theory that tobacco smoking could be a form of self-medicating of major depression, and moclobemide could therefore help increase abstinence rates due to moclobemide mimicking the MAO-A inhibiting effects of tobacco smoke. A 2023 Cochrane review found only one 1995 trial studying the effects of moclobemide on smoking cessation, it was administered for 3 months and then stopped; at 6 months follow-up it was found those who had taken moclobemide for 3 months had a much higher successful quit rate than those in the placebo group. However, at 12-month follow-up the difference between the placebo group and the moclobemide group was no longer significant.
  • Panic disorder: moclobemide is useful in the treatment and management of panic disorder. Panic disorder is mentioned as an accepted but unlicensed indication in the Australian Medicines Handbook.
  • ADHD: Two small studies assessing the benefit of moclobemide in people with attention deficit disorder found that moclobemide produced favourable results.
  • Fibromyalgia: moclobemide has been found to improve pain and functioning in this group of people.

Similar to other MAOIs, reversible MAOIs such as moclobemide may also be effective in a range of other psychiatric disorders. Menopausal flushing may also respond to moclobemide.

In efficacy studies for the treatment of major depressive disorder, moclobemide has been found to be significantly more effective than placebo, as effective as the tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs), and somewhat less effective than the older, irreversible MAOIs phenelzine and tranylcypromine. In terms of tolerability, however, moclobemide was found to be comparable to the SSRIs and better tolerated than the TCAs and older MAOIs. There is some evidence that moclobemide on its own or in combination with other antidepressants such as SSRIs is also effective for treatment resistant depression and that the combination can be administered without the development of serotonin syndrome; however, further research is needed before such a combination can be recommended. Follow-up studies show that ongoing use of antidepressants leads to continuing improvement in depression over time; and also have demonstrated that moclobemide retains its therapeutic efficacy as an antidepressant for at least a year. This long-term efficacy is equivalent to that seen with other antidepressant classes.

People on irreversible MAOIs have to discontinue these antidepressants two weeks before general anaesthesia, however, the use of moclobemide, due to its reversible nature, would allow such patients to possibly continue antidepressant therapy.

A dexamethasone suppression test (DST) and plasma and urine methoxyhydroxyphenylglycol (MHPG) test can be used to estimate who is likely to respond to moclobemide antidepressant therapy.

Pregnancy and Lactation

The doses of moclobemide in breast milk are very low (0.06% of moclobemide being recovered in breast milk) and therefore it has been concluded that moclobemide is unlikely to have any adverse effect on a suckling baby.

Children

Use in children is not recommended as there is insufficient data to assess safety and efficacy in these patients.

Elderly

Reversible MAOIs such as moclobemide may have advantages in the treatment of depression associated with Alzheimer’s disease due to its effect on noradrenaline. Cognitive impairments have been found to improve in people with dementia when depression is treated with moclobemide. Due to its superior safety profile, moclobemide has been recommended as a first line agent for the treatment of depression in the elderly. Due to the side effect profile of moclobemide, it may be a better option for this sub group of people than other antidepressants. Research has found evidence that moclobemide may be able to counter anti-cholinergic (Scopolamine) induced cognitive impairments thus making moclobemide a good choice in the depression in the elderly and those with dementia.

Adverse Effects

The incidence of adverse events is not correlated with age; however, adverse events occur more often in females than in males. Moclobemide is regarded as a generally safe antidepressant and due to its favourable side effect profile, it can be considered a first-line therapeutic antidepressant. The rate of incidence of side effects of moclobemide is low, with insomnia, headache and dizziness being the most commonly reported side effects in the initial stages of therapy with moclobemide. Moclobemide, even at high doses of 600 mg, does not impair the ability to drive a motor vehicle. The tolerability of moclobemide is similar in women and men and it is also well tolerated in the elderly. Moclobemide has been found to be superior to tricyclic and irreversible MAOI antidepressants in terms of side effects, as it does not cause anticholinergic, sedative or cardiovascular adverse effects.

Unlike the irreversible MAOIs there is no evidence of liver toxicity with moclobemide. Moclobemide has a similar efficacy profile compared to other antidepressants while being superior to the classic MAOIs and the tricyclics in terms of tolerance and safety profile. Moclobemide has little effect on psychomotor functions. Other side effects include nausea, insomnia, tremor and lightheadedness; orthostatic hypotension (dizziness upon standing) is uncommon even among the elderly. Behavioural toxicity or other impairments relating to everyday living does not occur with moclobemide, except that in doses of 400 mg or higher peripheral reaction time may be impaired. Peripheral oedema has been associated with moclobemide.

Some of the side effects are transient and disappear within 2 weeks of treatment. Serious fatigue, headache, restlessness, nervousness and sleep disturbances have been described as side effects from moclobemide therapy. A paradoxical worsening of depression has been reported in some individuals in several studies, and reports of suicide or suicidal ideation have been reported as a rare adverse effect of moclobemide. Overall, antidepressants decrease the risk of suicide. Moclobemide is believed to have only small proconvulsant effects; however, rarely seizures may occur. Hypertension has been reported to occur very rarely with moclobemide therapy.

Moclobemide is relatively well tolerated. The following are the potential adverse effects and their respective incidences:

Common (>1% incidence) Adverse Effects

  • Nausea
  • Dry mouth
  • Constipation
  • Diarrhoea
  • Insomnia
  • Dizziness
  • Anxiety
  • Restlessness

Uncommon/Rare (<1%) Adverse Effects

  • Difficulties falling asleep
  • Nightmares and vivid dreams
  • Hallucinations
  • Memory disturbances
  • Confusion
  • Disorientation
  • Delusions
  • Increased depression
  • Excitation/irritability
  • Hypomania
  • Mania
  • Aggressive behaviour
  • Apathy
  • Tension
  • Suicidal ideation
  • Suicidal behaviour
  • Migraine
  • Extrapyramidal effects
  • Tinnitus
  • Paraesthesia
  • Dysarthria
  • Heartburn
  • Gastritis
  • Tympany
  • Indigestion
  • Hypertension
  • Bradycardia
  • Extrasystoles
  • Angina/chest pain
  • Phlebetic symptoms
  • Flushing
  • Exanthema/rash
  • Allergic skin reaction
  • Itching
  • Gingivitis
  • Stomatitis
  • Dry skin
  • Conjunctivitis
  • Pruritus
  • Urticaria
  • Disturbances of micturition (dysuria, polyuria, tenesmus)
  • Metrorrhagia
  • Prolonged menstruation
  • General malaise
  • Skeletal/muscular pain
  • Altered taste sensations
  • Hot flushes/cold sensation
  • Photopsia
  • Dyspnoea
  • Visual disturbances
  • Increased hepatic enzymes without associated clinical sequelae.

Contraindications

Avoid use in:

  • Confusional states
  • Phaeochromocytoma

And caution is recommended in:

  • Agitated/excited patients
  • Thyrotoxicosis

Drug Interactions

Moclobemide has fewer interactions than irreversible MAOIs. Cimetidine however, causes a significant rise in moclobemide levels and therefore if the combination is used, lower doses of moclobemide have been recommended. There is little increase in the effects of alcohol when combined with moclobemide and, in fact, moclobemide causes a reduction in alcohol-related impairments. Moclobemide also interacts with pethidine/meperidine, and dextropropoxyphene. Ephedrine in combination with moclobemide increases the risk of cardiovascular adverse effects. Moclobemide is also likely to interact with warfarin. The combination of moclobemide with prescription or over the counter sympathomimetic drugs is not recommended due to the potential of significant drug interactions.

Serotonin syndrome has been reported when moclobemide has been taken in combination with other serotonin enhancing drugs; however, due to moclobemide’s reversible MAO inhibition, serotonin syndrome is significantly less likely to occur with moclobemide than with older irreversible MAOIs. Serotonin syndrome has been reported when trazodone was abruptly replaced with moclobemide. Taking at the same time or starting moclobemide too soon after discontinuing clomipramine or serotonin reuptake inhibitors such as SSRIs may result in the development of a serotonin syndrome. SNRIs such as venlafaxine in combination with moclobemide have also been associated with serotonin syndrome. Cimetidine causes a doubling of the blood plasma levels of moclobemide. Blood plasma levels of trimipramine and maprotiline and possibly other tricyclic antidepressants increase when used in combination with moclobemide and may require dosage adjustments if the combination is used for treatment resistant depression. The elimination of zolmitriptan is reduced by moclobemide and if the combination is used, a dosage reduction of zolmitriptan is recommended. Moclobemide reduces the metabolism of dextromethorphan. Moclobemide may decrease metabolism of diazepam, omeprazole, proguanil, propranolol and others due to inhibition of CYP2C19.

Dietary

Irreversible MAOIs can cause unpleasant and occasionally dangerous side effects such as a hypertensive crises after intake of food or drink containing indirectly acting sympathomimetic amines such as tyramine. This is sometimes referred to as the ‘cheese effect’. These side effects are due to irreversible inhibition of MAO in the gut and vasomotor neurones. However, the reversible MAOI antidepressants such as moclobemide have a very different side effect profile in this regard. The reversible binding to MAO-A by moclobemide allows amines such as tyramine to displace moclobemide from MAO-A allowing its metabolism and removing the risk of a hypertensive crisis that occurs with irreversible MAO inhibition. Of 2,300 people in multiple clinical trials who were treated with moclobemide in doses up to 600 mg with no dietary restrictions, none experienced a tyramine-mediated hypertensive reaction. As the pressor effect of moclobemide is so low, dietary restrictions are not necessary in people eating a normal diet, in contrast to irreversible MAOIs. However, some rare cheeses that have a high tyramine level may possibly cause a pressor effect and require caution. The potentiation of the pressor effect of tyramine by moclobemide is only one seventh to one tenth of that of irreversible MAOIs. In order to minimise this potentiation, postprandial administration (taken after meals) of moclobemide is recommended. The combined use of moclobemide and selegiline requires dietary restrictions as the combination can lead to increased sensitivity to the pressor effect of foods containing tyramine.

While moclobemide or the irreversible MAO-B selective inhibitor selegiline taken alone has very little pressor effect, and requires no dietary restriction, the combination of selegiline with moclobemide leads to a significant enhancement of the pressor effect and such a combination requires dietary restriction of foods containing high amounts of tyramine. The combination of moclobemide and a reversible MAO-B inhibitor requires tyramine dietary restrictions.

Overdose

Moclobemide is considered to be less toxic in overdose compared to older antidepressants, such as the tricyclic antidepressants and the irreversible and non-selective MAOIs, making it a safer antidepressant in the elderly or people with physical disorders. Of 18 people who overdosed on moclobemide during clinical trials, all recovered fully and moclobemide was judged to be safe for inpatient as well as outpatient use. Intoxications with moclobemide as single agent are usually mild; however, when combined with tricyclic or SSRI antidepressants the overdose is much more toxic and potentially fatal. Moclobemide, is preferred by doctors for patients who are at risk of suicide, due to moclobemide’s low toxicity in overdose. Patients with mixed intoxications (e.g. with other CNS active drugs) may show severe or life-threatening symptoms and should be hospitalised. Treatment is largely symptomatic and should be aimed at maintenance of the vital functions.

Withdrawal and Tolerance

Withdrawal symptoms appear to be very rare with moclobemide compared to other antidepressants; a single report of relatively mild flu-like symptoms persisting for 7 days after rapid reduction of high dose moclobemide therapy has been reported in one patient. Withdrawal of moclobemide causes a rebound in REM sleep.

Moclobemide does not seem to prevent withdrawal symptoms from serotonin reuptake inhibitors.

Discontinuation of moclobemide is recommended to be done gradually to minimise side effects (e.g. rapid return of condition being treated and/or the appearance of withdrawal symptoms). Tolerance to the therapeutic effects has been reported in a small number of users of MAOIs including moclobemide.

Pharmacology

Moclobemide is a benzamide, derivative of morpholine, which acts pharmacologically as a selective, reversible inhibitor of monoamine oxidase-A (RIMA), a type of monoamine oxidase inhibitor (MAOI), and increases levels of norepinephrine (noradrenaline), dopamine, and especially serotonin in neuronal cells as well as in synaptic vesicles; extracellular levels also increase which results in increased monoamine receptor stimulation and suppression of REM sleep, down regulation of beta-3 adrenergic receptors. Moclobemide’s primary action is to disable MAO-A enzymes from decomposing norepinephrine, serotonin, and dopamine which results in a rising level of these neurotransmitters. Although it has been estimated that a single 300 mg dose of moclobemide inhibits 80% of monoamine oxidase-A (MAO-A) and 20-30% of MAO-B, studies evaluating brain occupancy of MAO-A enzymes have shown dosages of 600 mg to only inhibit 74% of MAO-A enzymes and dosages in the 900–1200 mg range to inhibit slightly less MAO-A than phenelzine (Nardil) at 45–60 mg; subsequently, it is highly plausible that reports of lower efficacy could be largely or entirely the consequence of conservative dosage guidelines rather than the pharmacological properties of the drug. Previously, it was widely reported that both MAO-A and MAO-B enzymes were responsible for the metabolism of dopamine; however, new research suggests that MAO-B enzymes are involved in the generation of GABA and not the degradation of dopamine. There is also some evidence of moclobemide possessing neuroprotective properties in rodent models. There is no cumulative effect of moclobemide centrally when taken long-term. With long-term use of moclobemide, there is a significant down-regulation of B-adrenoceptors. Single or repeated dosing with 100–300 mg of moclobemide leads to a reduction in deaminated metabolites of amines such as 3,4-dihydroxyphenylacetic acid, 3,4-dihydroxyphenylethylglycol as well as 5-HIAA. Excretion of homovanillic acid and vanillylmandelic acid via urine is also reduced. There is also a temporary increase in prolactin during initial intake of 100–300 mg of moclobemide. L-dihydroxyphenylalanine is also reduced. Inhibition of the serotonin metabolite is less pronounced than the norepinephrine metabolite which suggests there are other major metabolic pathways for serotonin other than MAO-A.

It has been described as a ‘slow binding inhibitor’, whereby conformational changes to either moclobemide or the enzyme to MAO-A slowly form a more tightly bound complex, resulting in the non-competitive MAO inhibition by moclobemide. With three times daily dosing the inhibition on MAO-A was relatively constant with moclobemide. The MAO inhibition of moclobemide lasts about 8–10 hours and wears off completely by 24 hours after dosing. The inhibition of MAO-A by moclobemide is 10 times more potent than the irreversible MAOI phenelzine and approximately equivalent to tranylcypromine and isocarboxazid.

Moclobemide increases levels of extracellular monoamines and decreases levels of their metabolites in rat brains; tolerance to these effects does not seem to occur with chronic use of moclobemide. Moclobemide lacks anticholinergic effects and cognitive impairments can be improved by moclobemide. Moclobemide suppresses the unstimulated release of certain proinflammatory cytokines which are believed to be involved in the pathophysiology of major depression and stimulates the release of anti-inflammatory cytokines. Long-term treatment with moclobemide leads to an increase in cyclic adenosine monophosphate (cAMP) binding to cAMP-dependent protein kinase (PKA).

Moclobemide is chemically unrelated to irreversible MAOI antidepressants and only has a very weak pressor effect of orally administered tyramine. In humans, the n-oxide metabolites of moclobemide and moclobemide itself are the compounds that produce most of the inhibition of MAO-A; other metabolites are significantly less potent than the parent compound.

In healthy people moclobemide has a relatively small suppressing effect on REM sleep; in contrast, depressed people who have been treated with moclobemide, progressively show improved sleep over a 4-week period, with an increase in stage 2 non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep. There have been conflicting findings with regard to moclobemide altering cortisol levels and whether moclobemide increases growth hormone levels. Testosterone levels increase significantly with long-term use of moclobemide in depressed males.

Moclobemide also has neuroprotective properties in its demonstrated anti-hypoxia or anti-ischemia effects; there is a possibility that moclobemide may possess similar neuro-rescuing properties, similar to selegiline, however, research is required to determine this. Moclobemide has also been demonstrated in a single dose research study to possess antinociceptive properties.

Platelet MAO is of the MAO-B and this is inhibited only to a small degree in humans; the inhibition is due to low levels of metabolites of moclobemide that have MAO-B inhibiting properties. Moclobemide has been reported to be a mixed MAO-A/MAO-B inhibitor in rats but in man, it has been reported to be a pure MAO-A inhibitor, blocking the decomposition of norepinephrine, serotonin and, to a lesser extent, dopamine. No reuptake inhibition of any of the neurotransmitters occurs. The pharmacodynamic action encompasses activation, elevation of mood, and improvement of symptoms like dysphoria, fatigue, and difficulties in concentration. The duration and quality of sleep may be improved. In the treatment of depression the antidepressant effect often becomes evident in the first week of therapy (earlier than typically noted with TCAs/SSRIs).

MAO activity returns completely back to normal after 24 hours of the last dose, which allows for a quick switch to another antidepressant after the 24 hours.

Pharmacokinetics

In humans moclobemide is rapidly and almost completely absorbed and totally metabolised via the liver. Peak plasma levels occur 0.3 to 2 hours after oral administration. The bioavailability increases during the first week of therapy from 60% to 80% and more. The elimination half-life is around 2 hours. It is moderately bound to plasma proteins, especially albumin. However, the short disposition half life somewhat increases after repeated dosing; moclobemide has an intermediate elimination half life for systemic clearance and an intermediate volume of distribution. Despite its short half-life the pharmacodynamic action of a single dose persists for approximately 16 hours. The drug is almost completely metabolized in the liver; it is a substrate of CYP2C19 and an inhibitor of CYP2C19, CYP2D6 and CYP1A2. Less than 1% of the drug is excreted unchanged; 92% of the metabolised drug is excreted within the first 12 hours. The main metabolites are the N-oxide Ro 12-5637 formed via morpholine N-oxidation and lactam derivative Ro 12-8095 formed via morpholine C-oxidation; active metabolites are found only in trace amounts. The unchanged drug (less than 1%) as well as the metabolites are excreted renally (in urine). The main degradation pathway of moclobemide is oxidation. About 44% of the drug is lost due to the first pass effect through the liver. Age and renal function do not affect the pharmacokinetics of moclobemide. However, patients with significantly reduced liver function require dose reductions due to the significant slowing of metabolism of moclobemide. Food slows the absorption but does not affect the bioavailability of moclobemide.

Steady state concentrations are established after one week. It has been suggested that changes in dose should not be made with a gap of less than a week. Moclobemide has good penetration across the blood brain barrier with peak plasma levels within the central nervous system occurring 2 hours after administration.

Animal Toxicology

  • Acute toxicity: The oral LD50 values in mouse and rat are quite high, indicating a wide therapeutic index. LD50 for mice is 730 mg/kg and for rats 1,300 mg/kg. In dogs doses in excess of 300 mg/kg led to vomiting, salivation, ataxia, and drowsiness.
  • Chronic toxicity: In an 18-months-study in rats with 10 mg/kg no signs of chronic toxicity were noted, with 50 mg/kg and 250 mg/kg only a slight loss of weight, and with 250 mg/kg mildly elevated Alkaline phosphatase and Gamma-GT. Studies in dogs revealed no toxicity relevant for humans. No evidence for a possible hepatic or cardiovascular toxicity was found.

Society and Culture

The Australian TGA approved moclobemide in December 2000.

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What is Mirtazapine?

Published on by Andrew Marshall1 Comment

Introduction

Mirtazapine, sold under the brand name Remeron among others, is an atypical tetracyclic antidepressant, and as such is used primarily to treat depression. Its effects may take up to four weeks but can also manifest as early as one to two weeks. It is often used in cases of depression complicated by anxiety or insomnia. The effectiveness of mirtazapine is comparable to other commonly prescribed antidepressants. It is taken by mouth.

Common side effects include sleepiness, dizziness, increased appetite and weight gain. Serious side effects may include mania, low white blood cell count, and increased suicide among children. Withdrawal symptoms may occur with stopping. It is not recommended together with a monoamine oxidase inhibitor, although evidence supporting the danger of this combination has been challenged. It is unclear if use during pregnancy is safe. How it works is not clear, but it may involve blocking certain adrenergic and serotonin receptors. Chemically, it is a tetracyclic antidepressant, and is closely related to mianserin. It also has strong antihistaminergic effects.

Mirtazapine came into medical use in the United States in 1996. The patent expired in 2004, and generic versions are available. In 2022, it was the 105th most commonly prescribed medication in the United States, with more than 6 million prescriptions.

Brief History

Mirtazapine was first synthesized at Organon and published in 1989, was first approved for use in major depressive disorder in the Netherlands in 1994, and was introduced in the United States in 1996 under the brand name Remeron.

Medical Uses

Mirtazapine is approved by the United States Food and Drug Administration (FDA) for the treatment of major depressive disorder in adults.

Depression

Mirtazapine is primarily used for major depressive disorder and other mood disorders. Onset of action appears faster than some selective serotonin reuptake inhibitors (SSRIs) and similar to tricyclic antidepressants.

In 2010, the National Institute for Health and Care Excellence recommended generic SSRIs as first-line choices, as they are “equally effective as other antidepressants and have a favourable risk–benefit ratio.” For mirtazapine, it found:

“no difference between mirtazapine and other antidepressants on any efficacy measure, although in terms of achieving remission mirtazapine appears to have a statistical though not clinical advantage. In addition, mirtazapine has a statistical advantage over selective serotonin reuptake inhibitors in terms of reducing symptoms of depression, but the difference is not clinically significant. However, there is strong evidence that patients taking mirtazapine are less likely to leave treatment early because of side effects, although this is not the case for patients reporting side effects or leaving treatment early for any reason.”

A 2011 Cochrane review comparing mirtazapine to other antidepressants found that while it appeared to have a faster onset in people for whom it worked (measured at two weeks), its efficacy was about the same as other antidepressants after six weeks’ use.

A 2012 review focused on antidepressants and sleep found that mirtazapine reduced the time it took to fall asleep and improved the quality of sleep in many people with sleep disorders caused by depression, but that it could also disturb sleep in many people, especially at higher doses, causing restless leg syndrome in 8 to 28% of people and in rare cases causes REM sleep behaviour disorder. This seemingly paradoxical dose–response curve of mirtazapine with respect to somnolence is owed to the exceptionally high affinity of the drug for the histamine H1, 5-HT2A, and 5-HT2C receptors; exhibiting near exclusive occupation of these receptors at doses ≤15 mg. However, at higher doses, inverse agonism and constitutive activation of the α2A-, α2B-, and α2C-adrenergic receptors begins to offset activity at H1 receptors leading to decreased somnolence and even a subjective sensation of “activation” in treated patients.

A 2018 analysis of 21 antidepressants found them to be fairly similar overall. It found tentative evidence for mirtazapine being in the more effective group and middle in tolerability.

After one week of usage, mirtazapine was found to have an earlier onset of action compared to SSRIs.

Other

There is also some evidence supporting its use in treating the following conditions, for which it is sometimes prescribed off-label:

  • Generalised anxiety disorder (GAD)
  • Social anxiety disorder
  • Obsessive–compulsive disorder (OCD)
  • Panic disorder
  • Post-traumatic stress disorder (PTSD)
  • Low appetite/underweight
  • Insomnia
  • Nausea and vomiting
  • Itching
  • Headaches and migraine

Side or Adverse Effects

A 2011 Cochrane review found that, compared with other antidepressants, it is more likely to cause weight gain and sleepiness, but it is less likely to cause tremors than tricyclic antidepressants, and less likely to cause nausea and sexual dysfunction than SSRIs.

Very common (≥10% incidence) adverse effects include constipation, dry mouth, sleepiness, increased appetite (17%) and weight gain (>7% increase in <50% of children).

Common (1–10% incidence) adverse effects include weakness, confusion, dizziness, fasciculations (muscle twitches), peripheral oedema (swelling, usually of the lower limbs), and negative lab results like elevated transaminases, elevated serum triglycerides, and elevated total cholesterol.

Mirtazapine is not considered to have a risk of many of the side effects often associated with other antidepressants like the SSRIs and may improve certain ones when taken in conjunction with them. (Those adverse effects include decreased appetite, weight loss, insomnia, nausea and vomiting, diarrhoea, urinary retention, increased body temperature, excessive sweating, pupil dilation and sexual dysfunction.)

In general, some antidepressants, especially SSRIs, can paradoxically exacerbate some peoples’ depression or anxiety or cause suicidal ideation. Despite its sedating action, mirtazapine is also believed to be capable of this, so in the United States and certain other countries, it carries a black box label warning of these potential effects, especially for people under the age of 25.

Mirtazapine may induce arthralgia (non-inflammatory joint pain).

A case report published in 2000 noted an instance in which mirtazapine counteracted the action of clonidine, causing a dangerous rise in blood pressure.

In a study comparing 32 antidepressants of all pharmacological classes, mirtazapine was one of the antidepressants most likely to cause nightmare disorder, sleepwalking, restless legs syndrome, night terrors and sleep paralysis.

Mirtazapine has been associated with an increased risk of death compared to other antidepressants in several studies. However, it is more likely that the residual differences between people prescribed mirtazapine rather than a SSRI account for the difference in risk of mortality.

Withdrawal

Stopping Mirtazapine and other antidepressants may cause withdrawal symptoms. A gradual and slow reduction in dose is recommended to minimise such symptoms. Effects of sudden cessation of treatment with mirtazapine may include depression, anxiety, tinnitus, panic attacks, vertigo, restlessness, irritability, decreased appetite, insomnia, diarrhoea, nausea, vomiting, flu-like symptoms, allergy-like symptoms such as pruritus, headaches, and sometimes mania or hypomania.

Overdose

Mirtazapine is considered to be relatively safe in the event of an overdose, although it is considered slightly more toxic in overdose than most of the SSRIs (except citalopram). Unlike the tricyclic antidepressants, mirtazapine showed no significant cardiovascular adverse effects at 7 to 22 times the maximum recommended dose.

Twelve reported fatalities have been attributed to mirtazapine overdose. The fatal toxicity index (deaths per million prescriptions) for mirtazapine is 3.1 (95% CI: 0.1 to 17.2). This is similar to that observed with SSRIs.

Interactions

Concurrent use with inhibitors or inducers of the cytochrome P450 isoenzymes CYP1A2, CYP2D6, or CYP3A4 can result in altered concentrations of mirtazapine, as these are the main enzymes responsible for its metabolism. As examples, fluoxetine and paroxetine, inhibitors of these enzymes, are known to modestly increase mirtazapine levels, while carbamazepine, an inducer, considerably decreases them. Liver impairment and moderate chronic kidney disease have been reported to decrease the oral clearance of mirtazapine by about 30%; severe kidney disease decreases it by 50%.

Mirtazapine in combination with a SSRI, serotonin–norepinephrine reuptake inhibitor, or tricyclic antidepressant as an augmentation strategy is considered to be relatively safe and is often employed therapeutically but caution should be given when combined with fluvoxamine. There is a combination of venlafaxine and mirtazapine, sometimes referred to as “California rocket fuel”. Several case reports document serotonin syndrome induced by the combination of mirtazapine with other agents (olanzapine, quetiapine, tramadol and venlafaxine). Adding fluvoxamine to treatment with mirtazapine may cause a significant increase in mirtazapine concentration. This interaction may necessitate an adjustment of the mirtazapine dosage.

According to information from the manufacturers, mirtazapine should not be started within two weeks of any monoamine oxidase inhibitor usage; likewise, monoamine oxidase inhibitors should not be administered within two weeks of discontinuing mirtazapine.

The addition of mirtazapine to a monoamine oxidase inhibitor, while potentially having typical or idiosyncratic (unique to the individual) reactions not herein described, does not appear to cause serotonin syndrome. This is per the fact that the 5-HT2A receptor is the predominant serotonin receptor thought to be involved in the pathophysiology of serotonin syndrome (with the 5-HT1A receptor seeming to be protective). Mirtazapine is a potent 5-HT2A receptor antagonist, and cyproheptadine, a medication that shares this property, mediates recovery from serotonin syndrome and is an antidote against it.

There is a possible interaction that results in a hypertensive crisis when mirtazapine is given to a patient who has already been on steady doses of clonidine. This involves a subtle consideration, when patients have been on chronic therapy with clonidine and suddenly stop the dosing, a rapid hypertensive rebound sometimes (20%) occurs from increased sympathetic outflow. Clonidine’s blood pressure lowering effects are due to stimulation of presynaptic α2 autoreceptors in the CNS which suppress sympathetic outflow. Mirtazapine itself blocks these same α2 autoreceptors, so the effect of adding mirtazapine to a patient stabilised on clonidine may precipitate withdrawal symptoms.

Mirtazapine has been used as a hallucinogen antidote to block the effects of serotonergic psychedelics like psilocybin and lysergic acid diethylamide (LSD).

Pharmacology

Pharmacodynamics

Mirtazapine is sometimes described as a noradrenergic and specific serotonergic antidepressant (NaSSA), although the actual evidence in support of this label has been regarded as poor. It is a tetracyclic piperazine-azepine.

Mirtazapine has antihistamine, α2-blocker, and antiserotonergic activity. It is specifically a potent antagonist or inverse agonist of the α2A-, α2B-, and α2C-adrenergic receptors, the serotonin 5-HT2A, 5-HT2C, and the histamine H1 receptor. Unlike many other antidepressants, it does not inhibit the reuptake of serotonin, norepinephrine, or dopamine, nor does it inhibit monoamine oxidase. Similarly, mirtazapine has weak or no activity as an anticholinergic or blocker of sodium or calcium channels, in contrast to most tricyclic antidepressants. In accordance, it has better tolerability and low toxicity in overdose. As an H1 receptor antagonist, mirtazapine is extremely potent, and is in fact one of the most potent H1 receptor inverse agonists among tricyclic and tetracyclic antidepressants and most antihistamines in general. Antagonism of the H1 receptor is by far the strongest activity of mirtazapine, with the drug acting as a selective H1 receptor antagonist at low concentrations.

The (S)-(+) enantiomer of mirtazapine is responsible for antagonism of the serotonin 5-HT2A and 5-HT2C receptors, while the (R)-(–) enantiomer is responsible for antagonism of the 5-HT3 receptor. Both enantiomers are involved in antagonism of the H1 and α2-adrenergic receptors, although the (S)-(+) enantiomer is the stronger antihistamine.

Although not clinically relevant, mirtazapine has been found to act as a partial agonist of the κ-opioid receptor at high concentrations (EC50 = 7.2 μM).

α2-Adrenergic Receptor

Antagonism of the α2-adrenergic receptors, which function largely as inhibitory autoreceptors and heteroreceptors, enhances adrenergic and serotonergic neurotransmission, notably central 5-HT1A receptor mediated transmission in the dorsal raphe nucleus and hippocampus; hence, mirtazapine’s classification as a NaSSA. Indirect α1 adrenoceptor-mediated enhancement of serotonin cell firing and direct blockade of inhibitory α2 heteroreceptors located on serotonin terminals are held responsible for the increase in extracellular serotonin. Because of this, mirtazapine has been said to be a functional “indirect agonist” of the 5-HT1A receptor. Increased activation of the central 5-HT1A receptor is thought to be a major mediator of efficacy of most antidepressant drugs.

5-HT2 Receptor

Antagonism of the 5-HT2 subfamily of receptors and inverse agonism of the 5-HT2C receptor appears to be in part responsible for mirtazapine’s efficacy in the treatment of depressive states. Mirtazapine increases dopamine release in the prefrontal cortex. Accordingly, it was shown that by blocking the α2-adrenergic receptors and 5-HT2C receptors mirtazapine disinhibited dopamine and norepinephrine activity in these areas in rats. In addition, mirtazapine’s antagonism of 5-HT2A receptors has beneficial effects on anxiety, sleep and appetite, as well as sexual function regarding the latter receptor. Mirtazapine has been shown to lower drug seeking behaviour (more specifically to methamphetamine) in various human and animal studies. It is also being investigated in substance abuse disorders to reduce withdrawal effects and improve remission rates.

Mirtazapine significantly improves pre-existing symptoms of nausea, vomiting, diarrhoea, and irritable bowel syndrome in affected individuals. Mirtazapine may be used as an inexpensive antiemetic alternative to Ondansetron. In conjunction with substance abuse counselling, mirtazapine has been investigated for the purpose of reducing methamphetamine use in dependent individuals with success. In contrast to mirtazapine, the SSRIs, serotonin–norepinephrine reuptake inhibitors, monoamine oxidase inhibitors, and some tricyclic antidepressants acutely increase the general activity of the 5-HT2A, 5-HT2C, and 5-HT3 receptors, leading to a number of negative changes and side effects, the most prominent of which include anorexia, insomnia, nausea, and diarrhoea, among others. However, most of these adverse effects are temporary, since down regulation of 5-HT2A receptors eventually occurs following chronic SSRI treatment, and desensitisation of 5-HT3 receptors often occurs within a week or less. This is precisely why SSRIs have a delayed antidepressant and anxiolytic effect, and occasionally, an acute anxiogenic effect before down regulation occurs. Mirtazapine, on the other hand, is an antagonist of the 5-HT2A receptor, and antagonists at this receptor typically induce reverse tolerance. Thus, the antidepressant and anxiolytic effects of mirtazapine occur more rapidly than with SSRIs. Furthermore, its reduced incidence of sexual dysfunction (such as loss of libido and anorgasmia) could be a product of negligible binding to the serotonin transporter and antagonism of the 5-HT2A receptors; however, Mirtazapine’s high affinity towards and inverse agonism of the 5-HT2C receptors may greatly attenuate those pro-sexual factors (as evidenced by the pro-sexual effects of drugs like m-CPP and lorcaserin which agonise 5-HT2C receptors in a reasonably selective manner). As a result, it is often combined with these drugs to reduce their side-effect profile and to produce a stronger antidepressant effect.

Mirtazapine does not have pro-serotonergic activity and thus does not cause serotonin syndrome. This is in accordance with the fact that it is not a serotonin reuptake inhibitor or monoamine oxidase inhibitor, nor a serotonin receptor agonist. There are no reports of serotonin syndrome in association with mirtazapine alone, and mirtazapine has not been found to cause serotonin syndrome in overdose. However, there are a handful of case reports of serotonin syndrome occurring with mirtazapine in combination with serotonergic drugs like SSRIs, although such reports are very rare, and do not necessarily implicate mirtazapine as causative.

5-HT3 Receptor

(R)-(–)-mirtazapine is a potent 5-HT3 blocker. It may relieve chemotherapy-related and advanced cancer-related nausea.

H1 Receptor

Mirtazapine is a very strong H1 receptor antagonist and, as a result, it can cause powerful sedative and hypnotic effects. A single 15 mg dose of mirtazapine to healthy volunteers has been found to result in over 80% occupancy of the H1 receptor and to induce intense sleepiness. After a short period of chronic treatment, however, the H1 receptor tends to sensitise and the antihistamine effects become more tolerable. Many patients may also dose at night to avoid the effects, and this appears to be an effective strategy for combating them. Blockade of the H1 receptor may improve pre-existing allergies, pruritus, nausea, and insomnia in affected individuals. It may also contribute to weight gain, however. In contrast to the H1 receptor, mirtazapine has only low affinity for the muscarinic acetylcholine receptors, although anticholinergic side effects like dry mouth, constipation, and mydriasis are still sometimes seen in clinical practice.

Pharmacokinetics

The oral bioavailability of mirtazapine is about 50%. It is found mostly bound to plasma proteins, about 85%. It is metabolized primarily in the liver by N-demethylation and hydroxylation via cytochrome P450 enzymes, CYP1A2, CYP2D6, CYP3A4. The overall elimination half-life is 20–40 hours, and this is independent of dosage. It is conjugated in the kidney for excretion in the urine, where 75% of the drug is excreted, and about 15% is eliminated in faeces.  Desmethylmirtazapine is an active metabolite of mirtazapine which is believed to contribute about 3-10% to the drug’s overall effects and has a half-life of about 25 hours.

Chemistry

Mirtazapine is a tetracyclic piperazinoazepine; mianserin was developed by the same team of organic chemists and mirtazapine differs from it via the addition of a nitrogen atom in one of the rings. It is a racemic mixture of enantiomers. The (S)-(+)-enantiomer is known as esmirtazapine.

Analogues of mirtazapine include mianserin, setiptiline, and aptazapine.

Synthesis

A chemical synthesis of mirtazapine has been published. The first step of synthesis is a condensation reaction between the molecule 2-chloro 3-cyanopyridine and the molecule 1-methyl-3-phenylpiperazine.

Society and Culture

Generic Names

Mirtazapine is the English and French generic name of the drug and its INNTooltip International Nonproprietary Name, USANTooltip United States Adopted Name, USPTooltip United States Pharmacopeia, BANTooltip British Approved Name, DCFTooltip Dénomination Commune Française, and JANTooltip Japanese Accepted Name. Its generic name in Spanish, Italian, and Portuguese is mirtazapina and in German, Turkish and Swedish is mirtazapin.

Brand Names

Mirtazapine is marketed under many brand names worldwide, including Adco-Mirteron, Afloyan, Amirel, Arintapin Smelt, Avanza, Axit, Azapin, Beron, Bilanz, Blumirtax, Calixta, Ciblex, Combar, Comenter, Depreram, Divaril, Esprital, Maz, Menelat, Mepirzapine, Merdaten, Meronin, Mi Er Ning, Milivin, Minelza, Minivane, Mirastad, Mirazep, Miro, Miron, Mirrador, Mirt, Mirta, Mirtabene, Mirtadepi, Mirtagamma, Mirtagen, Mirtalan, Mirtamor, Mirtamylan, Mirtan, Mirtaneo, Mirtanza, Mirtapax, Mirtapil, Mirtapine, Mirtaron, Mirtastad, Mirtax, Mirtaz, Mirtazap, Mirtazapin, Mirtazapina, Mirtazapine, Mirtazapinum, Mirtazelon, Mirtazon, Mirtazonal, Mirtel, Mirtimash, Mirtin, Mirtine, Mirtor, Mirzapine, Mirzaten, Mirzest, Mitaprex, Mitaxind, Mitocent, Mitrazin, Mizapin, Motofen, Mytra, Norset, Noxibel, Pharmataz, Promyrtil, Rapizapine, Ramure, Razapina, Redepra, Reflex, Remergil, Remergon, Remeron, Remirta, Rexer, Saxib, Sinmaron, Smilon, Tazepin, Tazimed, Tetrazic, Tifona, U-Mirtaron, U-zepine, Valdren, Vastat, Velorin, Yarocen, Zania, Zapex, Zestat, Zismirt, Zispin, Zuleptan, and Zulin.

Research

The use of mirtazapine has been explored in several additional conditions:

  • Found ineffective for Sleep apnoea/hypopnoea.
  • Secondary symptoms of autistic spectrum conditions and other pervasive developmental disorders.
  • Antipsychotic-induced akathisia.
  • Drug withdrawal, dependence and detoxification.
  • Negative, depressive and cognitive symptoms of schizophrenia (as an adjunct).
  • A case report has been published in which mirtazapine reduced visual hallucinations in a patient with Parkinson’s disease psychosis (PDP). This is in alignment with recent findings that inverse agonists at the 5-HT2A receptors are efficacious in attenuating the symptoms of Parkinson’s disease psychosis. As is supported by the common practice of prescribing low-dose quetiapine and clozapine for PDP at doses too low to antagonise the D2 receptor, but sufficiently high doses to inversely agonise the 5-HT2A receptors.
  • Eight case reports have been reported in five papers on the use of mirtazapine in the treatment of hives as of 2017.
  • Mirtazapine to alleviate severe breathlessness in patients with COPD or interstitial lung diseases (BETTER-B). Found ineffective and potentially harmful.

Veterinary Use

Mirtazapine also has some veterinary use in cats and dogs. Mirtazapine is sometimes prescribed as an appetite stimulant for cats or dogs experiencing loss of appetite due to medical conditions such as chronic kidney disease. It is especially useful for treating combined poor appetite and nausea in cats and dogs.

Mirtazapine is indicated for bodyweight gain in cats experiencing poor appetite and weight loss resulting from chronic medical conditions.

There are two options for administration: tablets given orally, and an ointment applied topically to the inner surface of the ear.

The most common side effects include signs of local irritation or inflammation at the site where the ointment is applied and behavioural changes (increased meowing, hyperactivity, disoriented state or inability to coordinate muscle movements, lack of energy/weakness, attention-seeking, and aggression).

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

Published on by Andrew Marshall2 Comments

Introduction

Asociality refers to the lack of motivation to engage in social interaction, or a preference for solitary activities. Asociality may be associated with avolition, but it can, moreover, be a manifestation of limited opportunities for social relationships. Developmental psychologists use the synonyms non-social, unsocial, and social uninterest. Asociality is distinct from, but not mutually exclusive to, anti-social behaviour. A degree of asociality is routinely observed in introverts, while extreme asociality is observed in people with a variety of clinical conditions.

Asociality is not necessarily perceived as a totally negative trait by society, since asociality has been used as a way to express dissent from prevailing ideas. It is seen as a desirable trait in several mystical and monastic traditions, notably in Hinduism, Jainism, Roman Catholicism, Eastern Orthodoxy, Buddhism and Sufism.

Introversion

Introversion is “the state of or tendency toward being wholly or predominantly concerned with and interested in one’s own mental life.” Introverted persons are considered the opposite of extraverts, who seem to thrive in social settings rather than being alone. An introvert may present as an individual preferring being alone or interacting with smaller groups over interaction with larger groups, writing over speaking, having fewer but more fulfilling friendships, and needing time for reflection. While not a measurable personality trait, some popular writers have characterised introverts as people whose energy tends to expand through reflection and dwindle during interaction.

In matters of the brain, researchers have found differences in anatomy between introverted and extraverted persons. Introverted people are found to experience a higher flow of blood to the frontal lobe than extraverts, which is the part of the brain that contributes to problem-solving, memory, and pre-emptive thought.

Social Anhedonia

Social anhedonia is found in both typical and extreme cases of asociality or personality disorders that feature social withdrawal. Social anhedonia is distinct from introversion and is frequently accompanied with alexithymia.

Many cases of social anhedonia are marked by extreme social withdrawal and the complete avoidance of social interaction. One research article studying the individual differences in social anhedonia discusses the negative aspects of this form of extreme or aberrant asociality. Some individuals with social anhedonia are at higher risk of developing schizophrenia and may have mental functioning that becomes poorer than the average

In Human Evolution and Anthropology

Scientific research suggests that asocial traits in human behaviour, personality, and cognition may have several useful evolutionary benefits. Traits of introversion and aloofness can protect an individual from impulsive and dangerous social situations because of reduced impulsivity and reward. Frequent voluntary seclusion stimulates creativity and can give the individual time to think, work, reflect, and see useful patterns more easily.

Research indicates the social and analytical functions of the brain function in a mutually exclusive way. With this in mind, researchers posit that people who devoted less time or interest to socialisation used the analytical part of the brain more frequently and thereby were often responsible for devising hunting strategies, creating tools, and spotting useful patterns in the environment in general for both their own safety and the safety of the group.

Imitation and social learning have been confirmed to be potentially limiting and maladaptive in animal and human populations. When social learning overrides personal experience (asocial learning), negative effects can be observed such as the inability to seek or pick the most efficient way to accomplish a task and a resulting inflexibility to changing environments. Individuals who are less receptible, motivated, and interested in sociability are likely less affected by or sensible to socially imitated information and faster to notice and react to changes in the environment, essentially holding onto their own observations in a rigid manner and, consequently, not imitating a maladaptive behaviour through social learning. These behaviours, including deficits in imitative behaviour, have been observed in individuals with autism spectrum disorders and introverts, and are correlated with the personality traits of neuroticism and disagreeableness.

The benefits of this behaviour for the individual and their kin caused it to be preserved in part of the human population. The usefulness for acute senses, novel discoveries, and critical analytical thought may have culminated in the preservation of the suspected genetic factors of autism and introversion itself due to their increased cognitive, sensorial, and analytical awareness.

In Psychopathology

Schizophrenia

In schizophrenia, asociality is one of the main five “negative symptoms”, with the others being avolition, anhedonia, reduced affect, and alogia. Due to a lack of desire to form relationships, social withdrawal is common in people with schizophrenia. People with schizophrenia may experience social deficits or dysfunction as a result of the disorder, leading to asocial behaviour. Frequent or ongoing delusions and hallucinations can deteriorate relationships and other social ties, isolating individuals with schizophrenia from reality and in some cases leading to homelessness. Even when treated with medication for the disorder, they may be unable to engage in social behaviours. These behaviours include things like maintaining conversations, accurately perceiving emotions in others, or functioning in crowded settings. There has been extensive research on the effective use of social skills training (SST) for the treatment of schizophrenia, in outpatient clinics as well as inpatient units. SST can be used to help patients with schizophrenia make better eye contact with other people, increase assertiveness, and improve their general conversational skills.

Personality Disorders

Avoidant Personality Disorder

Asociality is common amongst people with avoidant personality disorder (AvPD). They experience discomfort and feel inhibited in social situations, being overwhelmed by feelings of inadequacy. Such people remain consistently fearful of social rejection, choosing to avoid social engagements as they do not want to give people the opportunity to reject (or possibly, accept) them. Though they inherently crave a sense of belonging, their fear of criticism and rejection leads people with AvPD to actively avoid occasions that require social interaction, leading to extremely asocial tendencies; as a result, these individuals often have difficulty cultivating and preserving close relationships.

People with AvPD may also display social phobia, the difference being that social phobia is the fear of social circumstances whereas AvPD is better described as an aversion to intimacy in relationships.

Schizoid Personality Disorder

Schizoid personality disorder (SzPD) is characterised by a lack of interest in social relationships, a tendency towards a solitary lifestyle, secretiveness, emotional coldness, and apathy. Affected individuals may simultaneously demonstrate a rich and elaborate but exclusively internal fantasy world.

It is not the same as schizophrenia, although they share such similar characteristics as detachment and blunted affect. There is, moreover, increased prevalence of the disorder in families with schizophrenia.

Schizotypal Personality Disorder

Schizotypal personality disorder is characterized by a need for social isolation, anxiety in social situations, odd behaviour and thinking, and often unconventional beliefs. People with this disorder feel extreme discomfort with maintaining close relationships with people, and therefore they often do not. People who have this disorder may display peculiar manners of talking and dressing and often have difficulty in forming relationships. In some cases, they may react oddly in conversations, not respond, or talk to themselves.

Autism

Autistic people may display profoundly asocial tendencies, due to differences in how autistic and allistic (non-autistic) people communicate. These different communication styles can cause mutual friction between the two neurotypes, known as the double empathy problem. Autistic people tend to express emotions differently and less intensely than allistic people, and often do not pick up on allistic social cues or linguistic pragmatics (including eye contact, facial expressions, tone of voice, body language, and implicatures) used to convey emotions and hints.

Connecting with others is important to overall health. An increased difficulty in accurately reading social cues by others can affect this desire for people with autism. The risk of adverse social experiences is high for those with autism, and so they may prefer to be avoidant in social situations rather than experience anxiety over social performance. Social deficits in people with autism is directly correlated with the increased prevalence of social anxiety in this community. As they are in a steep minority, there is risk of not having access to like-minded peers in their community, which can lead them to withdrawal and social isolation.

Mood Disorders

Depression

Asociality can be observed in individuals with major depressive disorder or dysthymia, as individuals lose interest in everyday activities and hobbies they used to enjoy, this may include social activities, resulting in social withdrawal and withdrawal tendencies.

SST can be adapted to the treatment of depression with a focus on assertiveness training. Depressed patients often benefit from learning to set limits with others, to obtain satisfaction for their own needs, and to feel more self-confident in social interactions. Research suggests that patients who are depressed because they tend to withdraw from others can benefit from SST by learning to increase positive social interactions with others instead of withdrawing from social interactions.

Social Anxiety Disorder

Asocial behaviour is observed in people with social anxiety disorder (SAD), who experience perpetual and irrational fears of humiliating themselves in social situations. They often have panic attacks and severe anxiety as a result, which can occasionally lead to agoraphobia. The disorder is common in children and young adults, diagnosed on average between the ages of 8 and 15. If left untreated, people with SAD exhibit asocial behaviour into adulthood, avoiding social interactions and career choices that require interpersonal skills. SST can help people with social phobia or shyness to improve their communication and social skills so that they will be able to mingle with others or go to job interviews with greater ease and self-confidence.

Traumatic Brain Injury

Traumatic brain injuries (TBI) can also lead to asociality and social withdrawal.

Management

Treatments

Social Skills Training

Social skills training (SST) is an effective technique aimed towards anyone with “difficulty relating to others,” a common symptom of shyness, marital and family conflicts, or developmental disabilities; as well as of many mental and neurological disorders including adjustment disorders, anxiety disorders, attention-deficit/hyperactivity disorder, social phobia, alcohol dependence, depression, bipolar disorder, schizophrenia, avoidant personality disorder, paranoid personality disorder, obsessive-compulsive disorder, and schizotypal personality disorder.

Fortunately for people who display difficulty relating to others, social skills can be learned, as they are not simply inherent to an individual’s personality or disposition. Therefore, there is hope for anyone who wishes to improve their social skills, including those with psychosocial or neurological disorders. Nonetheless, it is important to note that asociality may still be considered neither a character flaw nor an inherently negative trait.

SST includes improving eye contact, speech duration, frequency of requests, and the use of gestures, as well as decreasing automatic compliance to the requests of others. SST has been shown to improve levels of assertiveness (positive and negative) in both men and women.

Additionally, SST can focus on receiving skills (e.g. accurately perceiving problem situations), processing skills (e.g. considering several response alternatives), and sending skills (delivering appropriate verbal and non-verbal responses).

Metacognitive Interpersonal Therapy

Metacognitive interpersonal therapy is a method of treating and improving the social skills of people with personality disorders that are associated with asociality. Through metacognitive interpersonal therapy, clinicians seek to improve their patients’ metacognition, meaning the ability to recognise and read the mental states of themselves. The therapy differs from SST in that the patient is trained to identify their own thoughts and feelings as a means of recognising similar emotions in others. Metacognitive interpersonal therapy has been shown to improve interpersonal and decision-making skills by encouraging awareness of suppressed inner states, which enables patients to better relate to other people in social environments.

The therapy is often used to treat patients with two or more co-occurring personality disorders, commonly including obsessive-compulsive and avoidant behaviours.

Coping Mechanisms

In order to cope with asocial behaviour, many individuals, especially those with avoidant personality disorder, develop an inner world of fantasy and imagination to entertain themselves when feeling rejected by peers. Asocial people may frequently imagine themselves in situations where they are accepted by others or have succeeded at an activity. Additionally, they may have fantasies relating to memories of early childhood and close family members.

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

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Introduction

Iprindole, sold under the brand names Prondol, Galatur, and Tertran, is an atypical tricyclic antidepressant (TCA) that has been used in the United Kingdom and Ireland for the treatment of depression but appears to no longer be marketed.

It was developed by Wyeth and was marketed in 1967. The drug has been described by some as the first “second-generation” antidepressant to be introduced. However, it was very little-used compared to other TCAs, with the number of prescriptions dispensed only in the thousands.

Medical Uses

Iprindole was used in the treatment of major depressive disorder in dosages similar to those of other TCAs.

Contraindications

Iprindole has been associated with jaundice and hepatotoxicity and should not be taken by alcoholics or people with pre-existing liver disease. If such symptoms are encountered iprindole should be discontinued immediately.

Side Effects

Anticholinergic side effects such as dry mouth and constipation are either greatly reduced in comparison to imipramine and most other TCAs or fully lacking with iprindole. However, it still has significant antihistamine effects and therefore can produce sedation, though this is diminished relative to other TCAs similarly. Iprindole also lacks significant alpha-blocking properties, and hence does not pose a risk of orthostatic hypotension.

Overdose

Refer to Tricyclic Antidepressant Overdose.

In overdose, iprindole is much less toxic than most other TCAs and is considered relatively benign. For instance, between 1974 and 1985, only two deaths associated with iprindole were recorded in the United Kingdom, whereas 278 were reported for imipramine, although imipramine is used far more often than iprindole.

Interactions

Iprindole has been shown to be a potent inhibitor of the aromatic hydroxylation and/or N-dealkylation-mediated metabolism of many substances including, but not limited to octopamine, amphetamine, methamphetamine, fenfluramine, phenelzine, tranylcypromine, trimipramine, and fluoxetine, likely via inactivating cytochrome P450 enzymes. It also inhibits its own metabolism.

On account of these interactions, caution should be used when combining iprindole with other drugs. As an example, when administered with amphetamine or methamphetamine, iprindole increases their brain concentrations and prolongs their terminal half-lives by 2- to 3-fold, strongly augmenting both their physiological effects and neurotoxicity in the process.

Pharmacology

Pharmacodynamics

Iprindole is unique compared to most other TCAs in that it is a very weak and negligible inhibitor of the reuptake of serotonin and norepinephrine and appears to act instead as a selective albeit weak antagonist of 5-HT2 receptors; hence its classification by some as “second-generation”.

Additionally, iprindole has very weak/negligible antiadrenergic and anticholinergic activity and weak although possibly significant antihistamine activity; as such, side effects of iprindole are much less prominent relative to other TCAs, and it is well tolerated. However, iprindole may not be as effective as other TCAs, particularly in terms of anxiolysis. Based on animal research, the antidepressant effects of iprindole may be mediated through downstream dopaminergic mechanisms.

The binding affinities of iprindole for various biological targets are presented in the table to the right. It is presumed to act as an inhibitor or antagonist/inverse agonist of all sites. Considering the range of its therapeutic concentrations (e.g. 63–271 nM at 90 mg/day), only the actions of iprindole on the 5-HT2 and histamine receptors might be anticipated to be of possible clinical significance. However, it is unknown whether these actions are in fact responsible for the antidepressant effects of iprindole. The plasma protein binding of iprindole and hence its free percentage and potentially bioactive concentrations do not seem to be known.

Pharmacokinetics

Only one study appears to have evaluated the pharmacokinetics of iprindole. A single oral dose of 60 mg iprindole to healthy volunteers has been found to achieve mean peak plasma concentrations of 67.1 ng/mL (236 nmol/L) after 2 to 4 hours. The mean terminal half-life of iprindole was 52.5 hours, which is notably much longer than that of other TCAs like amitriptyline and imipramine. Following chronic treatment with 90 mg/day iprindole for 3 weeks, plasma concentrations of the drug ranged between 18 and 77 ng/mL (63–271 nmol/L). Theoretical steady-state concentrations should be reached by 99% within 15 to 20 days of treatment.

Chemistry

Iprindole is a tricyclic compound, specifically a cyclooctaindole (that is, an indole nucleus joined with a cyclooctyl ring), and possesses three rings fused together with a side chain attached in its chemical structure. It is a tertiary amine TCA, although its ring system and pharmacological properties are very different from those of other TCAs. Other tertiary amine TCAs that are similar to iprindole include butriptyline and trimipramine. The chemical name of iprindole is 3-(6,7,8,9,10,11-hexahydro-5H-cycloocta[b]indol-5-yl)-N,N-dimethylpropan-1-amine and its free base form has a chemical formula of C19H28N2 with a molecular weight of 284.439 g/mol. The drug has been used commercially as both the free base and the hydrochloride salt. The CAS Registry Number of the free base is 5560-72-5 and of the hydrochloride is 20432-64-8.

Society and Culture

Generic Names

Iprindole is the English and French generic name of the drug and its INN, USAN, BAN, and DCF, while iprindole hydrochloride is its BANM. Its generic name in Spanish and German is iprindol while its generic name in Latin is iprindolum. Iprindole was originally known unofficially as pramindole.

Brand Names

Iprindole has been marketed under the brand name Prondol by Wyeth in the United Kingdom and Ireland for the indication of major depressive disorder, and has also been sold as Galatur and Tertran by Wyeth.

Availability

Iprindole was previously available in the United Kingdom and Ireland but seems to no longer be available for medical use in any country.

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

Published on by Andrew Marshall1 Comment

Introduction

Dosulepin, also known as dothiepin and sold under the brand name Prothiaden among others, is a tricyclic antidepressant (TCA) which is used in the treatment of depression.

Dosulepin was once the most frequently prescribed antidepressant in the United Kingdom, but it is no longer widely used due to its relatively high toxicity in overdose without therapeutic advantages over other TCAs. It acts as a serotonin–norepinephrine reuptake inhibitor (SNRI) and also has other activities including antihistamine, antiadrenergic, antiserotonergic, anticholinergic, and sodium channel-blocking effects.

Brief History

Dosulepin was developed by SPOFA (then the largest producer of pharmaceutical products in the USSR). It was patented in 1962 and first appeared in the literature in 1962. The drug was first introduced for medical use in 1969, in the United Kingdom.

Medical Uses

Dosulepin is used for the treatment of major depressive disorder. There is clear evidence of the efficacy of dosulepin in psychogenic facial pain, though the drug may be needed for up to a year.

Contraindications

Contraindications include:

  • Epilepsy as it can lower the seizure threshold
  • TCAs should not be used concomitantly or within 14 days of treatment with monoamine oxidase inhibitors due to the risk for serotonin syndrome
  • Acute recovery phase following myocardial infarction as TCAs may produce conduction defects and arrhythmias
  • Liver failure
  • Hypersensitivity to dosulepin

Side Effects

Common Adverse Effects

  • Drowsiness
  • Extrapyramidal symptoms
  • Tremor
  • Disorientation
  • Dizziness
  • Paresthaesias
  • Alterations to ECG patterns
  • Dry mouth
  • Sweating
  • Urinary retention
  • Hypotension
  • Postural hypotension
  • Tachycardia
  • Palpitations
  • Arrhythmias
  • Conduction defects
  • Increased or decreased libido
  • Nausea
  • Vomiting
  • Constipation
  • Blurred vision

Less Common Adverse Effects

  • Disturbed concentration
  • Delusions
  • Hallucinations
  • Anxiety
  • Fatigue
  • Headaches
  • Restlessness
  • Excitement
  • Insomnia
  • Hypomania
  • Nightmares
  • Peripheral neuropathy
  • Ataxia
  • Incoordination
  • Seizures
  • Paralytic ileus
  • Hypertension
  • Heart block
  • Myocardial infarction
  • Stroke
  • Gynecomastia (swelling of breast tissue in males)
  • Testicular swelling
  • Impotence
  • Epigastric distress
  • Abdominal cramps
  • Parotid swellings
  • Diarrhea
  • Stomatitis (swelling of the mouth)
  • Black tongue
  • Peculiar taste sensations
  • Cholestatic jaundice
  • Altered liver function
  • Hepatitis (swelling of the liver)
  • Skin rash
  • Urticaria (hives)
  • Photosensitisation
  • Skin blisters
  • Angioneurotic edema
  • Weight loss
  • Urinary frequency
  • Mydriasis
  • Weight gain
  • Hyponatraemia (low blood sodium)
  • Movement disorders
  • Dyspepsia (indigestion)
  • Increased intraocular pressure
  • Changes in blood sugar levels
  • Thrombocytopenia (an abnormally low number of platelets in the blood. This makes one more susceptible to bleeds)
  • Eosinophilia (an abnormally high number of eosinophils in the blood)
  • Agranulocytosis (a dangerously low number of white blood cells in the blood leaving one open to potentially life-threatening infections)
  • Galactorrhoea (lactation that is non-associated with breastfeeding and lactation)

Overdose

Refer to Tricyclic Antidepressant Overdose.

The symptoms and the treatment of an overdose are largely the same as for the other TCAs. Dosulepin may be particularly toxic in overdose compared to other TCAs. The onset of toxic effects is around 4–6 hours after dosulepin is ingested. In order to minimise the risk of overdose it is advised that patients only receive a limited number of tablets at a time so as to limit their risk of overdosing. It is also advised that patients are not prescribed any medications that are known to increase the risk of toxicity in those receiving dosulepin due to the potential for mixed overdoses. The medication should also be kept out of reach of children.

Interactions

Dosulepin can potentiate the effects of alcohol and at least one death has been attributed to this combination. TCAs potentiate the sedative effects of barbiturates, tranquilisers and CNS depressants. Guanethidine and other adrenergic neuron blocking drugs can have their antihypertensive effects blocked by dosulepin. Sympathomimetics may potentiate the sympathomimetic effects of dosulepin. Due to the anticholinergic and antihistamine effects of dosulepin anticholinergic and antihistamine medications may have their effects potentiated by dosulepin and hence these combinations are advised against. Dosulepin may have its postural hypotensive effects potentiated by diuretics. Anticonvulsants may have their efficacy reduced by dosulepin due to its ability to reduce the seizure threshold.

Pharmacology

Pharmacodynamics

Dosulepin is a reuptake inhibitor of the serotonin transporter (SERT) and the norepinephrine transporter (NET), thereby acting as an SNRI. It is also an antagonist of the histamine H1 receptor, α1-adrenergic receptor, serotonin 5-HT2 receptors, and muscarinic acetylcholine receptors (mACh), as well as a blocker of voltage-gated sodium channels (VGSCs). The antidepressant effects of dosulepin are thought to be due to inhibition of the reuptake of norepinephrine and possibly also of serotonin.

Dosulepin has three metabolites, northiaden (desmethyldosulepin), dosulepin sulfoxide, and northiaden sulfoxide, which have longer terminal half-lives than that of dosulepin itself. However, whereas northiaden has potent activity similarly to dosulepin, the two sulfoxide metabolites have dramatically reduced activity. They have been described as essentially inactive, and are considered unlikely to contribute to either the therapeutic effects or side effects of dosulepin. Relative to dosulepin, northiaden has reduced activity as a serotonin reuptake inhibitor, antihistamine, and anticholinergic and greater potency as a norepinephrine reuptake inhibitor, similarly to other secondary amine TCAs. Unlike the sulfoxide metabolites, northiaden is thought to play an important role in the effects of dosulepin.

Although Heal & Cheetham (1992) reported relatively high Ki values of 12 and 15 nM for dosulepin and northiaden at the rat α2-adrenergic receptor and suggested that antagonism of the receptor could be involved in the antidepressant effects of dosulepin, Richelson & Nelson (1984) found a low KD of only 2,400 nM for dosulepin at this receptor using human brain tissue. This suggests that it in fact has low potency for this action, similarly to other TCAs.

Pharmacokinetics

Dosulepin is readily absorbed from the small intestine and is extensively metabolized on first-pass through the liver into its chief active metabolite, northiaden. Peak plasma concentrations of between 30.4 and 279 ng/mL (103–944 nmol/L) occur within 2–3 hours of oral administration. It is distributed in breast milk and crosses the placenta and blood–brain barrier. It is highly bound to plasma proteins (84%), and has a whole-body elimination half-life of 51 hours.

Chemistry

Dosulepin is a tricyclic compound, specifically a dibenzothiepine, and possesses three rings fused together with a side chain attached in its chemical structure. It is the only TCA with a dibenzothiepine ring system to have been marketed. The drug is a tertiary amine TCA, with its side chain-demethylated metabolite northiaden (desmethyldosulepin) being a secondary amine. Other tertiary amine TCAs include amitriptyline, imipramine, clomipramine, doxepin, and trimipramine. Dosulepin exhibits (E) and (Z) stereoisomerism like doxepin but in contrast the pure E or trans isomer is used medicinally. The drug is used commercially as the hydrochloride salt; the free base is not used.

Society and Culture

Generic Names

Dosulepin is the English and German generic name of the drug and its INN and BAN, while dosulepin hydrochloride is its BANM and JAN. Dothiepin is the former BAN of the drug while dothiepin hydrochloride is the former BANM and remains the current USAN. Its generic name in Spanish and Italian and its DCIT are dosulepina, in French and its DCF are dosulépine, and in Latin is dosulepinum.

Brand Names

Dosulepin is marketed throughout the world mainly under the brand name Prothiaden. It is or has been marketed under a variety of other brand names as well, including Altapin, Depresym, Dopress, Dothapax, Dothep, Idom, Prepadine, Protiaden, Protiadene, Thaden, and Xerenal.

Availability

Dosulepin is marketed throughout Europe (as Prothiaden, Protiaden, and Protiadene), Australia (as Dothep and Prothiaden), New Zealand (as Dopress) and South Africa (as Thaden). It is also available in Japan, Hong Kong, Taiwan, India, Singapore, and Malaysia. The drug is not available in the United States or Canada.

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