Tag: Treatment

What is Esmirtazapine?

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Introduction

Esmirtazapine (ORG-50,081) is a tetracyclic antidepressant drug which was under development by Organon for the treatment of insomnia and vasomotor symptoms (e.g. hot flashes) associated with menopause.

Outline

Esmirtazapine is the (S)-(+)-enantiomer of mirtazapine and possesses similar overall pharmacology, including inverse agonist actions at H1 and 5-HT2 receptors and antagonist actions at α2-adrenergic receptors.

Notably, esmirtazapine has a shorter half life of around 10 hours, compared to R-mirtazapine and racemic mixture, which has a half-life of 18-40 hours. Merck has run several studies on low dose (3 – 4.5 mg) esmirtazapine for the treatment of insomnia. It is attractive for treating insomnia since it is a potent H1-inhibitor and a 5-HT2A antagonist. Unlike low-dose mirtazapine, the half life (10 hours) is short enough that next-day sedation may be manageable, however, for people with CYP2D6 polymorphisms, which constitute a sizable fraction of the population, the half-life is expected to be quite a bit longer. Merck researchers claimed that the incidence of next-day sedation was not a problem in one of their studies, but this claim has been challenged (15% of patients complained of daytime sleepiness vs 3.5% in the placebo group).

In March 2010, Merck terminated its internal clinical development programme for esmirtazapine for hot flashes and insomnia, “for strategic reasons”.

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

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Introduction

Aptazapine (developmental code name CGS-7525A) is a tetracyclic antidepressant (TeCA) that was assayed in clinical trials for the treatment of depression in the 1980s but was never marketed.

Outline

It is a potent α2-adrenergic receptor antagonist with ~10x the strength of the related compound mianserin and has also been shown to act as a 5-HT2 receptor antagonist and H1 receptor inverse agonist, while having no significant effects on the reuptake of serotonin or norepinephrine.

Based on its pharmacological profile, aptazapine may be classified as a noradrenergic and specific serotonergic antidepressant (NaSSA).

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

Published on by Andrew Marshall4 Comments

Introduction

Trazodone, sold under many brand names, is an antidepressant medication. It is used to treat major depressive disorder, anxiety disorders, and difficulties with sleep. The medication is taken orally.

Common side-effects include dry mouth, feeling faint, vomiting, and headache. More serious side effects may include suicide, mania, irregular heart rate, and pathologically prolonged erections. It is unclear if use during pregnancy or breastfeeding is safe. It is a phenylpiperazine compound of the serotonin antagonist and reuptake inhibitor (SARI) class. Trazodone also has sedating effects.

Trazodone was approved for medical use in the United States in 1981. It is available as a generic medication. In 2020, it was the 21st most commonly prescribed medication in the United States, with more than 26 million prescriptions.

Brief History

Trazodone was developed in Italy, in the 1960s, by Angelini Research Laboratories as a second-generation antidepressant. It was developed according to the mental pain hypothesis, which was postulated from studying patients and which proposes that major depression is associated with a decreased pain threshold. In sharp contrast to most other antidepressants available at the time of its development, trazodone showed minimal effects on muscarinic cholinergic receptors. Trazodone was patented and marketed in many countries all over the world. It was approved by the Food and Drug Administration (FDA) in 1981 and was the first non-tricyclic or MAOI antidepressant approved in the US.

Medical Uses

Depression

The primary use of trazodone is the treatment of unipolar major depression with or without anxiety. Data from open and double-blind trials suggest the antidepressant efficacy of trazodone is comparable to that of amitriptyline, doxepin, and mianserin. Also, trazodone showed anxiolytic properties, low cardiotoxicity, and relatively mild side effects.

Because trazodone has minimal anticholinergic activity, it was especially welcomed as a treatment for geriatric patients with depression when it first became available. Three double-blind studies reported trazodone has antidepressant efficacy similar to that of other antidepressants in geriatric patients. However, a side effect of trazodone, orthostatic hypotension, which may cause dizziness and increase the risk of falling, can have devastating consequences for elderly patients; thus, this side effect, along with sedation, often makes trazodone less acceptable for this population, compared with newer compounds that share its lack of anticholinergic activity but not the rest of its side-effect profile. Still, trazodone is often helpful for geriatric patients with depression who have severe agitation and insomnia.

Trazodone is usually used at a dosage of 150 to 300 mg/day for the treatment of depression. Lower doses have also been used to augment other antidepressants, or when initiating therapy. Higher doses up to 600 mg/day have been used in more severe cases of depression, for instance in hospitalised patients. Trazodone is usually administered multiple times per day, but once-daily administration may be similarly effective.

Insomnia

Low-dose trazodone is used off-label in the treatment of insomnia and is considered to be effective and safe for this indication. It may also be used to treat antidepressant-related insomnia. Trazodone was the second-most prescribed agent for insomnia in the early 2000s, though most studies of trazodone for treatment of sleep disturbances have been in depressed individuals.

Systematic reviews and meta-analyses published in the late 2010s, including a Cochrane review, found low-dose trazodone to be an effective medication for short-term treatment of insomnia both in depressed and non-depressed people. Trazodone slightly improves subjective sleep quality (SMD = –0.34 to –0.41) and reduces number of nighttime awakenings (MD = –0.31, SMD = –0.51). Conversely, it does not appear to affect sleep onset, total sleep time, time awake after sleep onset, or sleep efficiency. It appears to increase deep sleep, in contrast to certain other hypnotics. The quality of evidence of trazodone for short-term treatment of insomnia was rated as low to moderate. There is no evidence available at present to inform long-term use of trazodone in the treatment of insomnia.

The benefits of trazodone for insomnia must be weighed against potential adverse effects such as morning grogginess, daytime sleepiness, cognitive and motor impairment, and postural hypotension, among others. Quality safety data on use of trazodone as a sleep aid are currently lacking.

Trazodone is used at low doses in the range of 25 to 150 mg/day for insomnia. Higher doses of 200 to 600 mg/day have also been studied.

The American Academy of Sleep Medicine’s 2017 clinical practice guidelines recommended against the use of trazodone in the treatment of insomnia due to inadequate evidence and due to harms potentially outweighing benefits.

Other Disorders

Trazodone is often used in the treatment of anxiety disorders such as generalised anxiety disorder, panic disorder, post-traumatic stress disorder (PTSD), and obsessive–compulsive disorder (OCD). However, use of trazodone in anxiety disorders is off-label and evidence of its effectiveness for these indications is variable and limited. Benefits for OCD appear to be mild. Besides anxiety, trazodone has been used to treat sleep disturbances and nightmares in PTSD. Trazodone is often used as an alternative to benzodiazepines in the treatment of anxiety disorders.

Combination with Other Antidepressants

Trazodone is often used in combination with other antidepressants such as selective serotonin reuptake inhibitors (SSRI) in order to augment their antidepressant and anxiolytic effects and to reduce side effects such as sexual dysfunction, anxiety, and insomnia.

Available Forms

Trazodone is provided as the hydrochloride salt and is available in the form of 50 mg, 100 mg, 150 mg, and 300 mg oral tablets.

An extended-release oral tablet formulation at doses of 150 mg and 300 mg is also available.

Side Effects

Because of its lack of anticholinergic side effects, trazodone is especially useful in situations in which antimuscarinic effects are particularly problematic (e.g. in patients with benign prostatic hyperplasia, closed-angle glaucoma, or severe constipation). Trazodone’s propensity to cause sedation is a dual-edged sword. For many patients, the relief from agitation, anxiety, and insomnia can be rapid; for other patients, including those individuals with considerable psychomotor retardation and feelings of low energy, therapeutic doses of trazodone may not be tolerable because of sedation. Trazodone elicits orthostatic hypotension in some people, probably as a consequence of α1-adrenergic receptor blockade. The unmasking of bipolar disorder may occur with trazodone and other antidepressants.

Precautions for trazodone include known hypersensitivity to trazodone and under 18 years and combined with other antidepressant medications, it may increase the possibility of suicidal thoughts or actions.

While trazodone is not a true member of the SSRI class of antidepressants, it does still share many properties of SSRIs, especially the possibility of discontinuation syndrome if the medication is stopped too quickly. Care must, therefore, be taken when coming off the medication, usually by a gradual process of tapering down the dose over a period of time.

Suicide

Antidepressants may increase the risk of suicidal thoughts and behaviours in children and young adults. Close monitoring for emergence of suicidal thoughts and behaviours is thus recommended.

Sedation

Since trazodone may impair the mental and/or physical abilities required for performance of potentially hazardous tasks, such as operating an automobile or machinery, the patient should be cautioned not to engage in such activities while impaired. Compared to the reversible MAOI antidepressant drug moclobemide, more impairment of vigilance occurs with trazodone. Trazodone has been found to impair driving ability.

Cardiac

Case reports have noted cardiac arrhythmias emerging in relation to trazodone treatment, both in patients with pre-existing mitral valve prolapse and in patients with negative personal and family histories of cardiac disease.

QT prolongation has been reported with trazodone therapy. Arrhythmia identified include isolated PVCs, ventricular couplets, and in two patients short episodes (three to four beats) of ventricular tachycardia. Several post-marketing reports have been made of arrhythmia in trazodone-treated patients who have pre-existing cardiac disease and in some patients who did not have pre-existing cardiac disease. Until the results of prospective studies are available, patients with pre-existing cardiac disease should be closely monitored, particularly for cardiac arrhythmias. Trazodone is not recommended for use during the initial recovery phase of myocardial infarction. Concomitant administration of drugs that prolong the QT interval or that are inhibitors of CYP3A4 may increase the risk of cardiac arrhythmia.

Priapism

A relatively rare side effect associated with trazodone is priapism, likely due to its antagonism at α-adrenergic receptors. More than 200 cases have been reported, and the manufacturer estimated that the incidence of any abnormal erectile function is about one in 6,000 male patients treated with trazodone. The risk for this side effect appears to be greatest during the first month of treatment at low dosages (i.e. <150 mg/day). Early recognition of any abnormal erectile function is important, including prolonged or inappropriate erections, and should prompt discontinuation of trazodone treatment. Spontaneous orgasms have also been reported with trazodone in men.

Clinical reports have described trazodone-associated psychosexual side effects in women as well, including increased libido, priapism of the clitoris, and spontaneous orgasms.

Others

Rare cases of liver toxicity have been observed, possibly due to the formation of reactive metabolites.

Elevated prolactin concentrations have been observed in people taking trazodone. They appear to be increased by around 1.5- to 2-fold.

Studies on trazodone and cognitive function are mixed, with some finding improvement, others finding no change, and some finding impairment.

Trazodone does not seem to worsen periodic limb movements during sleep.

Trazodone is associated with increased risk of falls in older adults. It has also been associated with increased risk of hip fractures in older adults.

Pregnancy and Lactation

Sufficient data in humans are lacking. Use should be justified by the severity of the condition to be treated.

Overdose

There are reported cases of high doses of trazodone precipitating serotonin syndrome. There are also reports of patients taking multiple SSRIs with trazodone and precipitating serotonin syndrome.

Trazodone appears to be relatively safer than TCAs, MAOIs, and a few of the other second-generation antidepressants in overdose situations, especially when it is the only agent taken. Fatalities are rare, and uneventful recoveries have been reported after ingestion of doses as high as 6,000–9,200 mg. In one report, 9 of 294 cases of overdose were fatal, and all nine patients had also taken other central nervous system (CNS) depressants. When trazodone overdoses occur, clinicians should carefully monitor for low blood pressure, a potentially serious toxic effect. In a report of a fatal trazodone overdose, torsades de pointes and complete atrioventricular block developed, along with subsequent multiple organ failure, with a trazodone plasma concentration of 25.4 mg/L on admission.

Interactions

Trazodone is metabolised by several liver enzymes, including CYP3A4, CYP2D6, and CYP1A2. Its active metabolite meta-chlorophenylpiperazine (mCPP) is known to be formed by CYP3A4 and metabolized by CYP2D6. Inhibition or induction of the aforementioned enzymes by various other substances may alter the metabolism of trazodone and/or mCPP, leading to increased and/or decreased blood concentrations. The enzymes in question are known to be inhibited and induced by many medications, herbs, and foods, and as such, trazodone may interact with these substances. Potent CYP3A4 inhibitors such as clarithromycin, erythromycin, fluvoxamine, grapefruit juice, ketoconazole, and ritonavir may lead to increased concentrations of trazodone and decreased concentrations of mCPP, while CYP3A4 inducers like carbamazepine, enzalutamide, phenytoin, phenobarbital, and St. John’s wort may result in decreased trazodone concentrations and increased mCPP concentrations. CYP2D6 inhibitors may result in increased concentrations of both trazodone and mCPP while CYP2D6 inducers may decrease their concentrations. Examples of potent CYP2D6 inhibitors include bupropion, cannabidiol, duloxetine, fluoxetine, paroxetine, quinidine, and ritonavir, while CYP2D6 inducers include dexamethasone, glutethimide, and haloperidol. CYP1A2 inhibitors may increase trazodone concentrations while CYP1A2 inducers may decrease trazodone concentrations. Examples of potent CYP1A2 inhibitors include ethinylestradiol (found in hormonal birth control), fluoroquinolones (e.g. ciprofloxacin), fluvoxamine, and St. John’s wort, while potent CYP1A2 inducers include phenytoin, rifampin, ritonavir, and tobacco.

A study found that ritonavir, a strong CYP3A4 and CYP2D6 inhibitor and moderate CYP1A2 inducer, increased trazodone peak levels by 1.34-fold, increased area-under-the-curve levels by 2.4-fold, and decreased the clearance of trazodone by 50%. This was associated with adverse effects such as nausea, hypotension, and syncope. Another study found that the strong CYP3A4 inducer carbamazepine reduced concentrations of trazodone by 60 to 74%. The strong CYP2D6 inhibitor thioridazine has been reported to increase concentrations of trazodone by 1.36-fold and concentrations of mCPP by 1.54-fold. On the other hand, CYP2D6 genotype has not been found to predict trazodone or mCPP concentrations with trazodone therapy, although it did correlate with side effects like dizziness and prolonged corrected QT interval.

Combination of trazodone with SSRIs, tricyclic antidepressants (TCAs), or monoamine oxidase inhibitors has a theoretical risk of serotonin syndrome. However, trazodone has been studied in combination with SSRIs and seemed to be safe in this context. On the other hand, cases of excessive sedation and serotonin syndrome have been reported with the combinations of trazodone and fluoxetine or paroxetine. This may be due to combined potentiation of the serotonin system. However, it may also be related to the fact that fluoxetine and paroxetine are strong inhibitors of CYP2D6 and fluoxetine is additionally a weak or moderate inhibitor of CYP3A4. Accordingly, fluoxetine has been reported to result in increased levels of trazodone and mCPP by 1.31- to 1.65-fold and by 2.97- to 3.39-fold, respectively.

Smokers have lower levels of trazodone and higher ratios of mCPP to trazodone. Trazodone levels were 30% lower in smokers and mCPP to trazodone ratio was 1.29-fold higher in smokers, whereas mCPP concentrations were not different between smokers and non-smokers. Smoking is known to induce CYP1A2, and this may be involved in these findings.

Pharmacology

Pharmacodynamics

Trazodone is a mixed agonist and antagonist of various serotonin receptors, antagonist of adrenergic receptors, weak histamine H1 receptor antagonist, and weak serotonin reuptake inhibitor. More specifically, it is an antagonist of 5-HT2A and 5-HT2B receptors, a partial agonist of the 5-HT1A receptor, and an antagonist of the α1- and α2-adrenergic receptors.It is also a ligand of the 5-HT2C receptor with lower affinity than for the 5-HT2A receptor. However, it is unknown whether trazodone acts as a full agonist, partial agonist, or antagonist of the 5-HT2C receptor. Trazodone is a 5-HT1A receptor partial agonist similarly to buspirone and tandospirone but with comparatively greater intrinsic activity. A range of weak affinities (Ki) have been reported for trazodone at the human histamine H1 receptor, including 220 nM, 350 nM, 500 nM, and 1,100 nM.

Trazodone has a minor active metabolite known as meta-chlorophenylpiperazine (mCPP), and this metabolite may contribute to some degree to the pharmacological properties of trazodone. In contrast to trazodone, mCPP is an agonist of various serotonin receptors. It has relatively low affinity for α1-adrenergic receptors unlike trazodone, but does high affinity for α2-adrenergic receptors and weak affinity for the H1 receptor. In addition to direct interactions with serotonin receptors, mCPP is a serotonin releasing agent similarly to agents like fenfluramine and MDMA. In contrast to these serotonin releasing agents however, mCPP does not appear to cause long-term serotonin depletion (a property thought to be related to serotonergic neurotoxicity).

Trazodone’s 5-HT2A receptor antagonism and weak serotonin reuptake inhibition form the basis of its common label as an antidepressant of the serotonin antagonist and reuptake inhibitor (SARI) type.

Target Occupancy Studies

Studies have estimated occupancy of target sites by trazodone based on trazodone concentrations in blood and brain and on the affinities of trazodone for the human targets in question. Roughly half of brain 5-HT2A receptors are blocked by 1 mg of trazodone and essentially all 5-HT2A receptors are saturated at 10 mg of trazodone, but the clinically effective hypnotic doses of trazodone are in the 25–100 mg range. The occupancy of the serotonin transporter (SERT) by trazodone is estimated to be 86% at 100 mg/day and 90% at 150 mg/day. Trazodone may almost completely occupy the 5-HT2A and 5-HT2C receptors at doses of 100 to 150 mg/day. Significant occupancy of a number of other sites may also occur. However, another study estimated much lower occupancy of the SERT and 5-HT2A receptors by trazodone.

Correspondence to Clinical Effects

Trazodone may act predominantly as a 5-HT2A receptor antagonist to mediate its therapeutic benefits against anxiety and depression. Its inhibitory effects on serotonin reuptake and 5-HT2C receptors are comparatively weak. In relation to these properties, trazodone does not have similar properties to SSRIs and is not particularly associated with increased appetite and weight gain – unlike other 5-HT2C antagonists like mirtazapine. Moderate 5-HT1A partial agonism may contribute to trazodone’s antidepressant and anxiolytic actions to some extent as well.

The combined actions of 5-HT2A and 5HT2C receptor antagonism with serotonin reuptake inhibition only occur at moderate to high doses of trazodone. Doses of trazodone lower than those effective for antidepressant action are frequently used for the effective treatment of insomnia. Low doses exploit trazodone’s potent actions as a 5-HT2A receptor antagonist, and its properties as an antagonist of H1 and α1-adrenergic receptors, but do not adequately exploit its SERT or 5-HT2C inhibition properties, which are weaker. Since insomnia is one of the most frequent residual symptoms of depression after treatment with an SSRI, a hypnotic is often necessary for patients with a major depressive episode. Not only can a hypnotic potentially relieve the insomnia itself, but treating insomnia in patients with major depression may also increase remission rates due to improvement of other symptoms such as loss of energy and depressed mood. Thus, the ability of low doses of trazodone to improve sleep in depressed patients may be an important mechanism whereby trazodone can augment the efficacy of other antidepressants.

Trazodone’s potent α1-adrenergic blockade may cause some side effects like orthostatic hypotension and sedation. Conversely, along with 5-HT2A and H1 receptor antagonism, it may contribute to its efficacy as a hypnotic. Trazodone lacks any affinity for the muscarinic acetylcholine receptors, so does not produce anticholinergic side effects.

mCPP, a non-selective serotonin receptor modulator and serotonin releasing agent, is an active metabolite of trazodone and has been suggested to possibly play a role in its therapeutic benefits. However, research has not supported this hypothesis and mCPP might actually antagonise the efficacy of trazodone as well as produce additional side effects.

Pharmacokinetics

Absorption

Trazodone is well-absorbed after oral administration. Its bioavailability is 65 to 80%. Peak blood levels of trazodone occur 1 to 2 hours after ingestion and peak levels of the metabolite mCPP occur after 2 to 4 hours. Absorption is somewhat delayed and enhanced by food.

Distribution

Trazodone is not sequestered into any tissue. The medication is 89 to 95% protein-bound. The volume of distribution of trazodone is 0.8 to 1.5 L/kg. Trazodone is highly lipophilic.

Metabolism

The metabolic pathways involved in the metabolism are not well-characterized. In any case, the cytochrome P450 enzymes CYP3A4, CYP2D6, and CYP1A2 may all be involved to varying extents. Trazodone is known to be extensively metabolized by the liver via hydroxylation, N-oxidation, and N-dealkylation. Several metabolites of trazodone have been identified, including a dihydrodiol metabolite (via hydroxylation), a metabolite hydroxylated at the para position of the meta-chlorophenyl ring (via CYP2D6), oxotriazolepyridinepropionic acid (TPA) and mCPP (both via N-dealkylation of the piperazinyl nitrogen mediated by CYP3A4), and a metabolite formed by N-oxidation of the piperazinyl nitrogen. CYP1A2, CYP2D6, and CYP3A4 genotypes all do not seem to predict concentrations of trazodone or mCPP. In any case, there are large interindividual variations in the metabolism of trazodone. In addition, poor metabolisers of dextromethorphan, a CYP2D6 substrate, eliminate mCPP more slowly and have higher concentrations of mCPP than do extensive metabolizers.

mCPP is formed from trazodone by CYP3A4 and is metabolised via hydroxylation by CYP2D6 (to a para-hydroxylated metabolite). It may contribute to the pharmacological actions of trazodone. mCPP levels are only 10% of those of trazodone during therapy with trazodone, but is nonetheless present at concentrations known to produce psychic and physical effects in humans when mCPP has been administered alone. In any case, the actions of trazodone, such as its serotonin antagonism, might partially overwhelm those of mCPP. As a consequence of the production of mCPP as a metabolite, patients administered trazodone may test positive on EMIT II urine tests for the presence of MDMA (“ecstasy”).

Elimination

The elimination of trazodone is biphasic: the first phase’s half-life (distribution) is 3 to 6 hours, and the following phase’s half-life (elimination) is 4.1 to 14.6 hours. The elimination half-life of extended-release trazodone is 9.1 to 13.2 hours. The elimination half-life of mCPP is 2.6 to 16.0 hours and is longer than that of trazodone. Metabolites are conjugated to gluconic acid or glutathione and around 70 to 75% of 14C-labelled trazodone was found to be excreted in the urine within 72 hours. The remaining drug and its metabolites are excreted in the faeces via biliary elimination. Less than 1% of the drug is excreted in its unchanged form. After an oral dose of trazodone, it was found to be excreted 20% in the urine as TPA and conjugates, 9% as the dihydrodiol metabolite, and less than 1% as unconjugated mCPP. mCPP is glucuronidated and sulfated similarly to other trazodone metabolites.

Chemistry

Trazodone is a triazolopyridine derivative and a phenylpiperazine that is structurally related to nefazodone and etoperidone, each of which are derivatives of it. Flibanserin is an analogue of trazodone.

Society and Culture

Generic Names

Trazodone is the generic name of the drug and its INN, BAN, and DCF, while trazodone hydrochloride is its USAN, USP, BANM, and JAN.

Brand Names

Trazodone has been marketed under a large number of brand names throughout the world. Major brand names include Desyrel (worldwide), Donaren (Brazil), Molipaxin (Ireland, United Kingdom), Oleptro (United States), Trazorel (Canada), and Trittico (worldwide).

Research

Trazodone may be effective in the treatment of sexual dysfunction, for instance female sexual dysfunction and erectile dysfunction. A 2003 systematic review and meta-analysis found some indication that trazodone may be useful in the treatment of erectile dysfunction. Besides trazodone alone, a combination of trazodone and bupropion (developmental code names and tentative brand names S1P-104, S1P-205, Lorexys, and Orexa) is under development for the treatment of erectile dysfunction and female sexual dysfunction. As of September 2021, it is in phase 2 clinical trials for these indications. It has been in this stage of clinical development since at least February 2015.

Trazodone may be useful in the treatment of certain symptoms like sleep disturbances in alcohol withdrawal and recovery. However, reviews have recommended against use of trazodone for alcohol withdrawal due to inadequate evidence. Very limited evidence suggests that trazodone might be useful in the treatment of certain symptoms in cocaine use disorder. Trazodone has been reported to be effective in the treatment of sleep apnoea. Cochrane reviews found that trazodone was not effective in the treatment of agitation in dementia. Another Cochrane review found that trazodone might be useful in the treatment of sleep disturbances in dementia. Further systematic reviews have found that trazodone may be effective for behavioural and psychological symptoms in dementias such as frontotemporal dementia and Alzheimer’s disease.

Trazodone has been studied as an adjunctive therapy in the treatment of schizophrenia. It has been reported to decrease negative symptoms without worsening positive symptoms although improvement in negative symptoms was modest. Trazodone has also been reported to be effective in treating antipsychotic-related extrapyramidal symptoms such as akathisia. Trazodone has been studied and reported to be effective in the treatment of bulimia, but there is limited evidence to support this use. It might be useful in the treatment of night eating disorder as well. Trazodone might be effective in the treatment of adjustment disorder. It may also be effective in the treatment of bruxism in children and adolescents.

Trazodone may be useful in the treatment of certain chronic pain disorders. There is limited but conflicting evidence to support the use of trazodone in the treatment of headaches and migraines in children. Trazodone may be useful in the treatment of fibromyalgia as well as diabetic neuropathy. It may also be useful in the treatment of burning mouth syndrome. A 2004 narrative review claimed that trazodone could be used in the treatment of complex regional pain syndrome. Trazodone may also be effective in the treatment of functional gastrointestinal disorders. It may be effective in the treatment of non-cardiac chest pain as well.

Trazodone may be useful in promoting motor recovery after stroke.

Veterinary Use

Trazodone has been used to reduce anxiety and stress, to improve sleep, and to produce sedation in dogs and cats in veterinary medicine.

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

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Introduction

Lorpiprazole (INN) (brand name Normarex) is a marketed anxiolytic drug of the phenylpiperazine group.

Outline

It has been described as a serotonin antagonist and reuptake inhibitor (SARI) in the same group as trazodone, nefazodone, and etoperidone.

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/Lorpiprazole >; 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 a Serotonin Reuptake Inhibitor?

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Introduction

A serotonin reuptake inhibitor (SRI) is a type of drug which acts as a reuptake inhibitor of the neurotransmitter serotonin (5-hydroxytryptamine, or 5-HT) by blocking the action of the serotonin transporter (SERT). This in turn leads to increased extracellular concentrations of serotonin and, therefore, an increase in serotonergic neurotransmission.

Outline

A SRI is a type of monoamine reuptake inhibitor (MRI); other types of MRIs include dopamine reuptake inhibitors and norepinephrine reuptake inhibitors.

SRIs are not synonymous with selective serotonin reuptake inhibitors (SSRIs), as the latter term is usually used to describe the class of antidepressants of the same name, and because SRIs, unlike SSRIs, can either be selective or non-selective in their action. For example, cocaine, which non-selectively inhibits the reuptake of serotonin, norepinephrine, and dopamine, is a SRI but not an SSRI.

SRIs are used predominantly as antidepressants (e.g., SSRIs, SNRIs, and TCAs), though they are also commonly used in the treatment of other psychological conditions such as anxiety disorders and eating disorders. Less often, SRIs are also used to treat a variety of other medical conditions including neuropathic pain and fibromyalgia (e.g. duloxetine, milnacipran), and premature ejaculation (e.g. dapoxetine) as well as for dieting (e.g. sibutramine). Additionally, some clinically used drugs such as chlorpheniramine, dextromethorphan, and methadone possess SRI properties secondarily to their primary mechanism of action(s) and this contributes to their side effect and drug interaction profiles.

A closely related type of drug is a serotonin releasing agent (SRA), an example of which is fenfluramine.

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/Serotonin_reuptake_inhibitor >; 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 a Serotonin Modulator and Stimulator?

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Introduction

A serotonin modulator and stimulator (SMS), sometimes referred to more simply as a serotonin modulator, is a type of drug with a multimodal action specific to the serotonin neurotransmitter system.

To be precise, SMSs simultaneously modulate one or more serotonin receptors and inhibit the reuptake of serotonin. The term was created to describe the mechanism of action of the serotonergic antidepressant vortioxetine, which acts as a serotonin reuptake inhibitor (SRI), agonist of the 5-HT1A receptor, and antagonist of the 5-HT3 and 5-HT7 receptors. However, it can also technically be applied to vilazodone, which is an antidepressant as well and acts as an SRI and 5-HT1A receptor partial agonist.

SMSs were developed because there are many different subtypes of serotonin receptors (at least 15 in total are currently known) and not all of these receptors appear to be involved in the antidepressant effects of SRIs. Some serotonin receptors seem to play a relatively neutral or insignificant role in the regulation of mood, but others, such as 5-HT1A autoreceptors and 5-HT7 receptors, appear to play an oppositional role in the efficacy of SRIs in treating depression. As such, a drug which combines the actions of, say, an SRI, 5-HT1A partial agonism, and 5-HT7 receptor antagonism, could, in theory, have the potential to prove more effective than pure SRIs. Alternatively, antagonism of 5-HT3 – a receptor that is involved in the regulation of nausea, vomiting, and the gastrointestinal tract – could counteract the undesirable increase in activation of this receptor mediated by SRIs, thereby potentially improving tolerability.

An alternative term is serotonin partial agonist/reuptake inhibitor (SPARI), which can be applied only to vilazodone.

It is similar to the marketing strategy used for the drug brexpiprazole, labelling it as a “serotonin-dopamine activity modulator” or ‘SDAM’.

Refer To

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What is a Serotonin Antagonist and Reuptake Inhibitor?

Published on by Andrew Marshall6 Comments

Introduction

Serotonin antagonist and reuptake inhibitors (SARIs) are a class of drugs used mainly as antidepressants, but also as anxiolytics and hypnotics. They act by antagonising serotonin receptors such as 5-HT2A and inhibiting the reuptake of serotonin, norepinephrine, and/or dopamine. Additionally, most also antagonise α1-adrenergic receptors. The majority of the currently marketed SARIs belong to the phenylpiperazine class of compounds.

List of SARIs

  • Marketed:
    • Etoperidone (Axiomin, Etonin)
    • Lorpiprazole (Normarex)
    • Mepiprazole (Psigodal)
    • Nefazodone (Serzone, Nefadar)
    • Trazodone (Desyrel)
  • Miscellaneous:
    • Vilazodone (Viibryd) – a related drug but does not fit into this class as it does not function as a serotonin antagonist, acting solely as a 5-HT1A receptor partial agonist instead.
    • Vortioxetine (Trintellix) – another closely related drug, could technically be considered to be a member of this group, but both vilazodone and vortioxetine are instead generally labeled as serotonin modulators and stimulators.
    • Niaprazine (Nopron) – a drug related to this group but does not inhibit the reuptake of serotonin or the other monoamines.
    • Medifoxamine (Clédial, Gerdaxyl) – could perhaps technically be said to belong to this group, as it is a serotonin–dopamine reuptake inhibitor and 5-HT2A and 5-HT2C receptor antagonist, but not grouped as such.
  • Never marketed:
    • Lubazodone (YM-992, YM-35995) – a SARI that was never marketed.

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What is an Noradrenergic and Specific Serotonergic Antidepressant?

Published on by Andrew Marshall4 Comments

Introduction

Noradrenergic and specific serotonergic antidepressants (NaSSAs) are a class of psychiatric drugs used primarily as antidepressants.

They act by antagonizing the α2-adrenergic receptor and certain serotonin receptors such as 5-HT2A and 5-HT2C, but also 5-HT3, 5-HT6, and/or 5-HT7 in some cases. By blocking α2-adrenergic autoreceptors and heteroreceptors, NaSSAs enhance adrenergic and serotonergic neurotransmission in the brain involved in mood regulation, notably 5-HT1A-mediated transmission. In addition, due to their blockade of certain serotonin receptors, serotonergic neurotransmission is not facilitated in unwanted areas, which prevents the incidence of many side effects often associated with selective serotonin reuptake inhibitor (SSRI) antidepressants; hence, in part, the “specific serotonergic” label of NaSSAs.

List of NaSSAs

The NaSSAs include the following agents:

  • Aptazapine (CGS-7525A)
  • Esmirtazapine (ORG-50,081)
  • Mianserin (Bolvidon, Norval, Tolvon)
  • Mirtazapine (Norset, Remeron, Avanza, Zispin)
  • Setiptiline/teciptiline (Tecipul)

Notably, all of these compounds are analogues and are also classified as tetracyclic antidepressants (TeCAs) based on their chemical structures.

S32212, a structurally novel NaSSA with an improved selectivity profile (e.g., no antihistamine effects, etc.), was reported in 2012. It has completed preliminary preclinical research and may go on to undergo clinical trials.

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What is Mianserin?

Published on by Andrew Marshall8 Comments

Introduction

Mianserin, sold under the brand name Tolvon among others, is an atypical antidepressant that is used primarily in the treatment of depression in Europe and elsewhere in the world.

It is a tetracyclic antidepressant (TeCA). Mianserin is closely related to mirtazapine, both chemically and in terms of its actions and effects, although there are significant differences between the two drugs.

Brief History

It was developed but not discovered by Organon International; the first patents were issued in The Netherlands in 1967, and it was launched in France in 1979 under the brand name Athymil, and soon thereafter in the UK as Norval. Investigators conducting clinical trials in the US submitted fraudulent data, and it was never approved in the US.

Mianserin was one of the first antidepressants to reach the UK market that was less dangerous than the tricyclic antidepressants in overdose; as of 2012 it was not prescribed much in the UK.

Medical Uses

Mianserin at higher doses (30–90mg/day) is used for the treatment of major depressive disorder.

It can also be used at lower doses (around 10mg/day) to treat insomnia.

Contraindications

It should not be given, except if based on clinical need and under strict medical supervision, to people younger than 18 years old, as it can increase the risk of suicide attempts and suicidal thinking, and it can increase aggressiveness.

While there is no evidence that it can harm a foetus from animal models, there are no data showing it safe for pregnant women to take.

People with severe liver disease should not take mianserin, and it should be used with caution for people with epilepsy or who are at risk for seizures, as it can lower the threshold for seizures. If based on clinical decision, normal precautions should be exercised and the dosages of mianserin and any concurrent therapy kept under review and adjusted as needed.

Side Effects

Very common (incidence > 10%) adverse effects include constipation, dry mouth, and drowsiness at the beginning of treatment.

Common (1% < incidence ≤ 10%) adverse effects include drowsiness during maintenance therapy, tremor, headache, dizziness, vertigo, and weakness.

Uncommon (0.1% < incidence ≤ 1%) adverse effects include weight gain.

Withdrawal

Abrupt or rapid discontinuation of mianserin may provoke a withdrawal, the effects of which may include depression, anxiety, panic attacks, decreased appetite or anorexia, insomnia, diarrhoea, nausea and vomiting, and flu-like symptoms, such as allergies or pruritus, among others.

Overdose

Overdose of mianserin is known to produce sedation, coma, hypotension or hypertension, tachycardia, and QT interval prolongation.

Interactions

Mianserin may enhance the sedative effects of drugs such as alcohol, anxiolytics, hypnotics, or antipsychotics when co-administered. It may decrease the efficacy of antiepileptic medications.

Carbamazepine and phenobarbital will cause the body to metabolise mianserin faster and may reduce its effects. There is a risk of dangerously low blood pressure if people take mianserin along with diazoxide, hydralazine, or nitroprusside. Mianserin can make antihistamines and antimuscarinics have stronger effects. Mianserin should not be taken with apraclonidine, brimonidine, sibutramine, or the combination drug of artemether with lumefantrine.

Pharmacology

Pharmacodynamics

Mianserin appears to exert its effects via antagonism of histamine and serotonin receptors, and inhibition of norepinephrine reuptake. More specifically, it is an antagonist/inverse agonist at most or all sites of the histamine H1 receptor, serotonin 5-HT1D, 5-HT1F, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3, 5-HT6, and 5-HT7 receptors, and adrenergic α1- and α2-adrenergic receptors, and additionally a norepinephrine reuptake inhibitor. As an H1 receptor inverse agonist with high affinity, mianserin has strong antihistamine effects (e.g., sedation). Conversely, it has low affinity for the muscarinic acetylcholine receptors, and hence lacks anticholinergic properties. Mianserin has been found to be a low affinity but potentially significant partial agonist of the κ-opioid receptor (Ki = 1.7 μM; EC50 = 0.53 μM), similarly to some tricyclic antidepressants (TCAs).

Blockade of the H1 and possibly α1-adrenergic receptors has sedative effects, and also antagonism of the 5-HT2A and α1-adrenergic receptors inhibits activation of intracellular phospholipase C (PLC), which seems to be a common target for several different classes of antidepressants. By antagonising the somatodendritic and presynaptic α2-adrenergic receptors, which function predominantly as inhibitory autoreceptors and heteroreceptors, mianserin disinhibits the release of norepinephrine, dopamine, serotonin, and acetylcholine in various areas of the brain and body.

Along with mirtazapine, although to a lesser extent in comparison, mianserin has sometimes been described as a noradrenergic and specific serotonergic antidepressant (NaSSA). However, the actual evidence in support of this label has been regarded as poor.

Pharmacokinetics

The bioavailability of mianserin is 20 to 30%. Its plasma protein binding is 95%. Mianserin is metabolised in the liver by the CYP2D6 enzyme via N-oxidation and N-demethylation. Its elimination half-life is 21 to 61 hours. The drug is excreted 4 to 7% in the urine and 14 to 28% in faeces.

Chemistry

Mianserin is a tetracyclic piperazinoazepine. Mirtazapine was developed by the same team of organic chemists and differs via addition of a nitrogen atom in one of the rings. (S)-(+)-Mianserin is approximately 200–300 times more active than its enantiomer (R)-(−)-mianserin; hence, the activity of mianserin lies in the (S)-(+) isomer.

Society and Culture

Generic Names

Mianserin is the English and German generic name of the drug and its INN and BAN, while mianserin hydrochloride is its USAN, BANM, and JAN. Its generic name in French and its DCF are miansérine, in Spanish and Italian and its DCIT are mianserina, and in Latin is mianserinum.

Brand Names

Mianserin is marketed in many countries mainly under the brand name Tolvon. It is also available throughout the world under a variety of other brand names including Athymil, Bonserin, Bolvidon, Deprevon, Lantanon, Lerivon, Lumin, Miansan, Serelan, Tetramide, and Tolvin among others.

Availability

Mianserin is not approved for use in the United States, but is available in the United Kingdom and other European countries. A mianserin generic drug received TGA approval in May 1996 and is available in Australia.

Research

The use of mianserin to help people with schizophrenia who are being treated with antipsychotics has been studied in clinical trials; the outcome is unclear.

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What is Methylphenidate?

Published on by Andrew Marshall2 Comments

Introduction

Methylphenidate, sold under the brand names Ritalin and Concerta among others, is a central nervous system (CNS) stimulant used medically to treat attention deficit hyperactivity disorder (ADHD) and, to a lesser extent, narcolepsy. It is a primary medication for ADHD (e.g. in the UK); it may be taken by mouth or applied to the skin, and different formulations have varying durations of effect, commonly ranging from 2–4 hours.

Common adverse reactions of methylphenidate include: tachycardia, palpitations, headache, insomnia, anxiety, hyperhidrosis, weight loss, decreased appetite, dry mouth, nausea, and abdominal pain. Withdrawal symptoms may include: chills, depression, drowsiness, dysphoria, exhaustion, headache, irritability, lethargy, nightmares, restlessness, suicidal thoughts, and weakness.

Methylphenidate is believed to work by blocking the reuptake of dopamine and norepinephrine by neurons. It is a central nervous system (CNS) stimulant of the phenethylamine and piperidine classes.

Etymology

The word methylphenidate is a portmanteau of the chemical name, Methyl-2-phenyl-2-(piperidin-2-yl) acetate.

Brief History

Methylphenidate was first synthesized in 1944 was approved for medical use in the United States in 1955. It was synthesized by chemist Leandro Panizzon and sold by Swiss company CIBA (now Novartis). He named the drug after his wife Margarita, nicknamed Rita, who used Ritalin to compensate for low blood pressure. Methylphenidate was not reported to be a stimulant until 1954. The drug was introduced for medical use in the United States in 1957. Originally, it was marketed as a mixture of two racemates, 80% (±)-erythro and 20% (±)-threo, under the brand name Centedrin. Subsequent studies of the racemates showed that the central stimulant activity is associated with the threo racemate and were focused on the separation and interconversion of the erythro isomer into the more active threo isomer. The erythro isomer was eliminated and now modern formulations of methyphenidate contain only the threo isomer at a 50:50 mixture of d- and l-isomers.

Methylphenidate was first used to allay barbiturate-induced coma, narcolepsy and depression. It was later used to treat memory deficits in the elderly. Beginning in the 1960s, it was used to treat children with ADHD based on earlier work starting with the studies by American psychiatrist Charles Bradley on the use of psychostimulant drugs, such as Benzedrine, with then called “maladjusted children”. Production and prescription of methylphenidate rose significantly in the 1990s, especially in the United States, as the ADHD diagnosis came to be better understood and more generally accepted within the medical and mental health communities.

In 2000, Alza Corporation received US FDA (Food and Drug Administration) approval to market Concerta, an extended-release form of methylphenidate.

It was estimated that the number of doses of methylphenidate used globally in 2013 increased by 66% compared to 2012. In 2020, it was the 41st most commonly prescribed medication in the United States, with more than 15 million prescriptions. It is available as a generic medication.

Uses

Methylphenidate is most commonly used to treat ADHD and narcolepsy.

Attention Deficit Hyperactivity Disorder

Methylphenidate is used for the treatment of attention deficit hyperactivity disorder. The addition of behavioural modification therapy can have additional benefits on treatment outcome. The dosage may vary and is titrated to effect, with some guidelines recommending initial treatment with a low dose. Immediate-release methylphenidate is used daily along with the longer-acting form to achieve full-day control of symptoms. Methylphenidate is not approved for children under six years of age.

In children over age 6 and adolescents, the short-term benefits and cost effectiveness of methylphenidate are well established. A number of reviews have established the safety and effectiveness for individuals with ADHD over several years.

Approximately 70% of those who use methylphenidate see improvements in ADHD symptoms. Children with ADHD who use stimulant medications generally have better relationships with peers and family members, perform better in school, are less distractible and impulsive, and have longer attention spans. There is evidence to suggest that children diagnosed with ADHD who do not receive treatment will have an increased risk of substance use disorders as adults.

The precise magnitude of improvement in ADHD symptoms and quality of life produced by methylphenidate treatment remains uncertain as of March 2023. Methylphenidate is not included in the World Health Organisation (WHO) Essential Medicines List, as findings by the WHO indicate evidence of benefit versus harm to be unclear in the treatment of ADHD. A 2021 systematic review did not find clear evidence for using IR methylphenidate (immediate-release) for adults.[34]

Since ADHD diagnosis has increased around the world, methylphenidate may be misused as a “study drug” by some populations, which may be harmful. This also applies to people who may be experiencing a different issue and are misdiagnosed with ADHD. People in this category can then experience negative side-effects of the drug which worsen their condition.

Narcolepsy

Narcolepsy, a chronic sleep disorder characterised by overwhelming daytime drowsiness and uncontrollable sleep, is treated primarily with stimulants. Methylphenidate is considered effective in increasing wakefulness, vigilance, and performance. Methylphenidate improves measures of somnolence on standardised tests, such as the Multiple Sleep Latency Test (MSLT), but performance does not improve to levels comparable to healthy people.

Other Medical Uses

Methylphenidate may also be prescribed for off-label use in treatment-resistant cases of bipolar disorder and major depressive disorder. It can also improve depression in several groups including stroke, cancer, and HIV-positive patients. There is weak evidence in favour of methylphenidate’s effectiveness for depression, including providing additional benefit in combination with antidepressants. In individuals with terminal cancer, methylphenidate can be used to counteract opioid-induced somnolence, to increase the analgesic effects of opioids, to treat depression, and to improve cognitive function. A 2021 systematic review and meta-analysis found that all studies on geriatric depression reported positive results of methylphenidate use; the review recommended short-term use in combination with citalopram. A 2018 review found low quality evidence supporting its use to treat apathy as seen in Alzheimer’s disease in addition to slight benefits for cognition and cognitive performance.

Enhancing Performance

Methylphenidate’s efficacy as a athletic performance enhancer, cognitive enhancer, aphrodisiac, and euphoriant is supported by research. However, the manner in which methylphenidate is used for these purposes (high doses and temperatures, alternate routes of administration, etc.) can result in severe unintended side effects. A 2015 review found that therapeutic doses of amphetamine and methylphenidate result in modest improvements in cognition, including working memory, episodic memory, and inhibitory control, in normal healthy adults; the cognition-enhancing effects of these drugs are known to occur through the indirect activation of both dopamine receptor D1 and adrenoceptor α2 in the prefrontal cortex. Methylphenidate and other ADHD stimulants also improve task saliency and increase arousal. Stimulants such as amphetamine and methylphenidate can improve performance on difficult and boring tasks, and are used by some students as a study and test-taking aid. Based upon studies of self-reported illicit stimulant use, performance-enhancing use rather than use as a recreational drug, is the primary reason that students use stimulants.

Excessive doses of methylphenidate, above the therapeutic range, can interfere with working memory and cognitive control. Like amphetamine and bupropion, methylphenidate increases stamina and endurance in humans primarily through reuptake inhibition of dopamine in the central nervous system. Similar to the loss of cognitive enhancement when using large amounts, large doses of methylphenidate can induce side effects that impair athletic performance, such as rhabdomyolysis and hyperthermia. While literature suggests it might improve cognition, most authors agree that using the drug as a study aid when ADHD diagnosis is not present does not actually improve GPA. Moreover, it has been suggested that students who use the drug for studying may be self-medicating for potentially deeper underlying issues.

Contraindications

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

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

Adverse Effects

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

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

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

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

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

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

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

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

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

Overdose

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

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

Addiction and Dependence

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

Biomolecular Mechanisms

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

Interactions

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

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

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

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

Pharmacology

Pharmacodynamics

Methylphenidate primarily acts as a norepinephrine–dopamine reuptake inhibitor (NDRI). It is a benzylpiperidine and phenethylamine derivative which also shares part of its basic structure with catecholamines.

Methylphenidate is a psychostimulant and increases the activity of the central nervous system through inhibition on reuptake of the neurotransmitters norepinephrine and dopamine. As models of ADHD suggest, it is associated with functional impairments in some of the brain’s neurotransmitter systems, particularly those involving dopamine in the mesocortical and mesolimbic pathways and norepinephrine in the prefrontal cortex and locus coeruleus. Psychostimulants like methylphenidate and amphetamine may be effective in treating ADHD because they increase neurotransmitter activity in these systems. When reuptake of those neurotransmitters is halted, its concentration and effects in the synapse increase and last longer, respectively. Therefore, methylphenidate is called a norepinephrine–dopamine reuptake inhibitor. By increasing the effects of norepinephrine and dopamine, methylphenidate increases the activity of the central nervous system and produces effects such as increased alertness, reduced fatigue, and improved attention.

Methylphenidate is most active at modulating levels of dopamine (DA) and to a lesser extent norepinephrine (NE). Methylphenidate binds to and blocks dopamine transporters (DAT) and norepinephrine transporters (NET). Variability exists between DAT blockade, and extracellular dopamine, leading to the hypothesis that methylphenidate amplifies basal dopamine activity, leading to nonresponse in those with low basal DA activity. On average, methylphenidate elicits a 3–4 times increase in dopamine and norepinephrine in the striatum and prefrontal cortex. Magnetic resonance imaging (MRI) studies suggest that long-term treatment with ADHD stimulants (specifically, amphetamine and methylphenidate) decreases abnormalities in brain structure and function found in subjects with ADHD.

Both amphetamine and methylphenidate are predominantly dopaminergic drugs, yet their mechanisms of action are distinct. Methylphenidate acts as a norepinephrine–dopamine reuptake inhibitor, while amphetamine is both a releasing agent and reuptake inhibitor of dopamine and norepinephrine. Methylphenidate’s mechanism of action in the release of dopamine and norepinephrine is fundamentally different from most other phenethylamine derivatives, as methylphenidate is thought to increase neuronal firing rate, whereas amphetamine reduces firing rate, but causes monoamine release by reversing the flow of the monoamines through monoamine transporters via a diverse set of mechanisms, including TAAR1 activation and modulation of VMAT2 function, among other mechanisms. The difference in mechanism of action between methylphenidate and amphetamine results in methylphenidate inhibiting amphetamine’s effects on monoamine transporters when they are co-administered.

Methylphenidate has both dopamine transporter and norepinephrine transporter binding affinity, with the dextromethylphenidate enantiomers displaying a prominent affinity for the norepinephrine transporter. Both the dextrorotary and levorotary enantiomers displayed receptor affinity for the serotonergic 5HT1A and 5HT2B subtypes, though direct binding to the serotonin transporter was not observed. A later study confirmed the d-threo-methylphenidate (dexmethylphenidate) binding to the 5HT1A receptor, but no significant activity on the 5HT2B receptor was found.

There exist some paradoxical findings that oppose the notion that methylphenidate acts as silent antagonist of the DAT (DAT inhibitor). 80% occupancy of the DAT is necessary for methylphenidate’s euphoriant effect, but re-administration of methylphenidate beyond this level of DAT occupancy has been found to produce similarly potent euphoriant effects (despite DAT occupancy being unchanged with repeated administration). By contrast, other DAT inhibitors such as bupropion have not been observed to exhibit this effect. These observations help corroborate the hypothesis that methylphenidate may act as a “DAT inverse agonist” or “negative allosteric modifier of the DAT” by reversing the direction of the dopamine efflux by the DAT at higher dosages.

Methylphenidate may protect neurons from the neurotoxic effects of Parkinson’s disease and methamphetamine use disorder. The hypothesized mechanism of neuroprotection is through inhibition of methamphetamine–DAT interactions, and through reducing cytosolic dopamine, leading to decreased production of dopamine-related reactive oxygen species.

The dextrorotary enantiomers are significantly more potent than the levorotary enantiomers, and some medications therefore only contain dexmethylphenidate. The studied maximised daily dosage of OROS methylphenidate appears to be 144 mg/day.

Pharmacokinetics

Methylphenidate taken by mouth has a bioavailability of 11–52% with a duration of action around 2–4 hours for instant-release (i.e. Ritalin), 3–8 hours for sustained-release (i.e. Ritalin SR), and 8–12 hours for extended-release (i.e. Concerta). The half-life of methylphenidate is 2–3 hours, depending on the individual. The peak plasma time is achieved at about 2 hours. Methylphenidate has a low plasma protein binding of 10–33% and a volume of distribution of 2.65 L/kg.

Dextromethylphenidate is much more bioavailable than levomethylphenidate when administered orally, and is primarily responsible for the psychoactivity of racemic methylphenidate.

The oral bioavailability and speed of absorption for immediate-release methylphenidate is increased when administered with a meal. The effects of a high fat meal on the observed Cmax differ between some extended-release formulations, with combined IR/ER and OROS formulations showing reduced Cmax levels while liquid-based extended-release formulations showed increased Cmax levels when administered with a high-fat meal, according to some researchers. A 2003 study, however, showed no difference between a high-fat meal administration and a fasting administration of oral methylphenidate.

Methylphenidate is metabolised into ritalinic acid by CES1A1 enzymes in the liver. Dextromethylphenidate is selectively metabolised at a slower rate than levomethylphenidate. 97% of the metabolised drug is excreted in the urine, and between 1 and 3% is excreted in the faeces. A small amount, less than 1%, of the drug is excreted in the urine in its unchanged form.

Society and Culture

Names

Methylphenidate is sold in the majority of countries worldwide.  Brand names for methylphenidate include Ritalin (in honour to Rita, the wife of the molecule discoverer), Rilatine (in Belgium to avoid a conflict of commercial name with the RIT pharmaceutical company), Concerta, Medikinet, Adaphen, Addwize, Inspiral, Methmild, Artige, Attenta, Cognil, Equasym, Foquest, Methylin, Penid, Phenida, Prohiper, and Tradea.

Available Forms

The dextrorotary enantiomer of methylphenidate, known as dexmethylphenidate, is sold as a generic and under the brand names Focalin and Attenade in both an immediate-release and an extended-release form. In some circumstances it may be prescribed instead of methylphenidate; however, it has no significant advantages over methylphenidate at equally potent doses, and so it is sometimes considered to be an example of an “evergreened” drug.

Immediate-Release

Methylphenidate was originally available as an immediate-release racemic mixture formulation under the Novartis brand name Ritalin, although a variety of generics are available, some under other brand names. Generic brand names include Ritalina, Rilatine, Attenta, Medikinet, Metadate, Methylin, Penid, Tranquilyn, and Rubifen.

Extended-Release

Concerta tablets are marked with the letters “ALZA” and followed by: “18”, “27”, “36”, or “54”, relating to the dosage strength in milligrams. Approximately 22% of the dose is immediate-release, and the remaining 78% of the dose is released over 10–12 hours post-ingestion, with an initial increase over the first 6 to 7 hours, and subsequent decline in released drug.

Ritalin LA capsules are marked with the letters “NVR” (abbrev.: Novartis) and followed by: “R20”, “R30”, or “R40”, depending on the (mg) dosage strength. Ritalin LA provides two standard doses – half the total dose being released immediately and the other half released four hours later. In total, each capsule is effective for about eight hours.

Metadate CD capsules contain two types of beads; 30% are immediate-release, and the other 70% are evenly sustained release.

Medikinet Retard/CR/Adult/Modified Release tablets is an extended-release oral capsule form of methylphenidate. It delivers 50% of dosage as IR MPH and the remaining 50% in 3–4 hours.

Skin Patch

A methylphenidate skin patch is sold under the brand name Daytrana in the United States. It was developed and marketed by Noven Pharmaceuticals and approved in the US in 2006. It is also referred to as methylphenidate transdermal system (MTS). It is approved as a once-daily treatment in children with ADHD aged 6–17 years. It is mainly prescribed as a second-line treatment when oral forms are not well tolerated, or if people have difficulty with compliance. Noven’s original FDA submission indicated that it should be used for 12 hours. When the FDA rejected the submission, they requested evidence that a shorter time period was safe and effective; Noven provided such evidence and it was approved for a 9-hour period.

Orally administered methylphenidate is subject to first-pass metabolism, by which the levo-isomer is extensively metabolised. By circumventing this first-pass metabolism, the relative concentrations of ℓ-threo-methylphenidate are much higher with transdermal administration (50–60% of those of dexmethylphenidate instead of about 14–27%).

A 39 nanograms/mL peak serum concentration of methylphenidate has been found to occur between 7.5–10.5 hours after administration. However, the onset to peak effect is 2 hours, and the clinical effects remain up to 2 hours after the patch has been removed. The absorption is increased when the transdermal patch is applied onto inflamed skin or skin that has been exposed to heat. The absorption lasts for approximately 9 hours after application (onto normal, unexposed to heat and uninflamed skin). 90% of the medication is excreted in the urine as metabolites and unchanged drug.

Parenteral Formulation

When it was released in the United States, methylphenidate was available from CIBA in a parenteral for use by medical professionals. It came in 10mL multiple dose vials containing 100 mg methylphenidate HCl and 100 mg lactose in lyophilized (freeze-dried) form. It was also available as single dose ampoules of containing 20 mg methylphenidate HCl. Instructions were to reconstitute with 10mL sterile solvent (water). The indication was 10 to 20 mg (1.0mL from MDV’s, up to one full single use ampoule) to produce a focused, talkative state that could help certain patients breakdown the resistance to therapy. Parenteral methylphenidate was discounted out of a concern for the actual benefit and of inducing a psychic dependence. This is not truth serum in the normal sense as it does not impair ability to control the flow of information like a barbiturate agent (Pentothal©) or similar might.

Cost

Brand-name and generic formulations are available.

Legal Status

  • Internationally, methylphenidate is a Schedule II drug under the Convention on Psychotropic Substances.
  • In the United States, methylphenidate is classified as a Schedule II controlled substance, the designation used for substances that have a recognised medical value but present a high potential for misuse.
  • In the United Kingdom, methylphenidate is a controlled ‘Class B’ substance. Possession without prescription carries a sentence up to 5 years or an unlimited fine, or both; supplying methylphenidate is 14 years or an unlimited fine, or both.
  • In Canada, methylphenidate is listed in Schedule III of the Controlled Drugs and Substances Act and is illegal to possess without a prescription, with unlawful possession punishable by up to three years imprisonment, or (via summary conviction) by up to one year imprisonment and/or fines of up to two thousand dollars. Unlawful possession for the purpose of trafficking is punishable by up to ten years imprisonment, or (via summary conviction) by up to eighteen months imprisonment.
  • In New Zealand, methylphenidate is a ‘class B2 controlled substance’. Unlawful possession is punishable by six-month prison sentence and distribution by a 14-year sentence.
  • In Australia, methylphenidate is a ‘Schedule 8’ controlled substance. Such drugs must be kept in a lockable safe until dispensed and possession without prescription is punishable by fines and imprisonment.
  • In Russia, methylphenidate is a List I controlled psychotropic substance without recognized medical value. The Constant Committee for Drug Control of the Russian Ministry of Health has put methylphenidate and its derivatives on the National List of Narcotics, Psychotropic Substances and Their Precursors, and the Government banned methylphenidate for any use on 25 October 2014.
  • In Sweden, methylphenidate is a List II controlled substance with recognized medical value. Possession without a prescription is punishable by up to three years in prison.
  • In France, methylphenidate is covered by the “narcotics” schedule, prescription and distribution conditions are restricted with hospital-only prescription for the initial treatment and yearly consultations.
  • In India, methylphenidate is a schedule X drug and is controlled by the Drugs and Cosmetics Rule, 1945. It is dispensed only by physician’s prescription. Legally, 2 grams of methylphenidate is classified as a small quantity, and 50 grams as a large or commercial quantity.
  • In Hong Kong, methylphenidate is controlled under the schedule 1 of the Dangerous Drugs Ordinance (cap. 134).

Controversy

Methylphenidate has been the subject of controversy in relation to its use in the treatment of ADHD. The prescription of psychostimulant medication to children to reduce ADHD symptoms has been a major point of criticism. The contention that methylphenidate acts as a gateway drug has been discredited by multiple sources, according to which abuse is statistically very low and “stimulant therapy in childhood does not increase the risk for subsequent drug and alcohol abuse disorders later in life”. A study found that ADHD medication was not associated with increased risk of cigarette use, and in fact stimulant treatments such as Ritalin seemed to lower this risk. People treated with stimulants such as methylphenidate during childhood were less likely to have substance use disorders in adulthood.

Among countries with the highest rates of use of methylphenidate medication is Iceland, where research shows that the drug was the most commonly used substance among people who inject drugs. The study involved 108 people who inject drugs and 88% of them had injected methylphenidate within the last 30 days and for 63% of them, methylphenidate was the most preferred substance.

Treatment of ADHD by way of methylphenidate has led to legal actions, including malpractice suits regarding informed consent, inadequate information on side effects, misdiagnosis, and coercive use of medications by school systems.

Research

Methylphenidate may be effective as a treatment for apathy in Alzheimer’s disease.

Replacement Therapy

Methylphenidate has shown some benefits as a replacement therapy for individuals who are addicted to and dependent upon methamphetamine. Methylphenidate and amphetamine have been investigated as a chemical replacement for the treatment of cocaine addiction. Its effectiveness in treatment of cocaine, psychostimulant addiction or psychological dependence has not been proven.

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