Tag: SSRI: Selective Serotonin Reuptake Inhibitors

What is Azapirone?

Published on by Andrew Marshall2 Comments

Introduction

Azapirones are a class of drugs used as anxiolytics, antidepressants, and antipsychotics. They are commonly used as add-ons to other antidepressants, such as selective serotonin reuptake inhibitors (SSRIs).

List of Azapirones

The azapirones include the following agents:

Anxiolytics

Antipsychotics

Others

  • SNAP-8719 (CAS number: 255893-38-0 )
  • CID:14086451

Medical Uses

Azapirones have shown benefit in general anxiety and augmenting SSRIs in social anxiety and depression. Evidence is not clear for panic disorder and functional gastrointestinal disorders.

Tandospirone has also been used to augment antipsychotics in Japan as it improves cognitive and negative symptoms of schizophrenia. Buspirone is being investigated for this purpose as well.

Side Effects

Side effects of azapirones may include dizziness, headaches, restlessness, nausea, and diarrhoea.

Azapirones have more tolerable adverse effects than many other available anxiolytics, such as benzodiazepines or SSRIs. Unlike benzodiazepines, azapirones lack abuse potential and are not addictive, do not cause cognitive/memory impairment or sedation, and do not appear to induce appreciable tolerance or physical dependence. However, azapirones are considered less effective with slow onset in controlling symptoms.

Chemistry

Buspirone was originally classified as an azaspirodecanedione, shortened to azapirone or azaspirone due to the fact that its chemical structure contained this moiety, and other drugs with similar structures were labelled as such as well. However, despite all being called azapirones, not all of them actually contain the azapirodecanedione component, and most in fact do not or contain a variation of it. Additionally, many azapirones are also pyrimidinylpiperazines, though again this does not apply to them all.

Drugs classed as azapirones can be identified by their -spirone or -pirone suffix.

Pharmacology

Pharmacodynamics

On a pharmacological level, azapirones varyingly possess activity at the following receptors:

  • 5-HT1A receptor (as partial or full agonists)
  • 5-HT2A receptor (as inverse agonists)
  • D2 receptor (as antagonists or partial agonists)
  • α1-adrenergic receptor (as antagonists)
  • α2-adrenergic receptor (as antagonists)

Actions at D4, 5-HT2C, 5-HT7, and sigma receptors have also been shown for some azapirones.

While some of the listed properties such as 5-HT2A and D2 blockade may be useful in certain indications such as in the treatment of schizophrenia (as with perospirone and tiospirone), all of them except 5-HT1A agonism are generally undesirable in anxiolytics and only contribute to side effects. As a result, further development has commenced to bring more selective of anxiolytic agents to the market. An example of this initiative is gepirone, which was recently approved after completing clinical trials in the United States for the treatment of major depression and generalised anxiety disorder. Another example is tandospirone which has been licensed in Japan for the treatment of anxiety and as an augmentation to antidepressants for depression.

5-HT1A receptor partial agonists have demonstrated efficacy against depression in rodent studies and human clinical trials. Unfortunately, however, their efficacy is limited and they are only relatively mild antidepressants. Instead of being used as monotherapy treatments, they are more commonly employed as augmentations to serotonergic antidepressants like the SSRIs. It has been proposed that high intrinsic activity at 5-HT1A postsynaptic receptors is necessary for maximal therapeutic benefits to come to prominence, and as a result, investigation has commenced in azapirones which act as 5-HT1A receptor full agonists such as alnespirone and eptapirone. Indeed, in preclinical studies, eptapirone produces robust antidepressant effects which surpass those of even high doses of imipramine and paroxetine.

Pharmacokinetics

Azapirones are poorly but nonetheless appreciably absorbed and have a rapid onset of action, but have only very short half-lives ranging from 1–3 hours. As a result, they must be administered 2–3 times a day. The only exception to this rule is umespirone, which has a very long duration with a single dose lasting as long as 23 hours. Unfortunately, umespirone has not been commercialised. Although never commercially produced, Bristol-Myers Squibb applied for a patent on 28 October 1993, and received the patent on 11 July 1995, for an extended release formulation of buspirone. An extended release formulation of gepirone is currently under development and if approved, should help to improve this issue.

Metabolism of azapirones occurs in the liver and they are excreted in urine and feces. A common metabolite of several azapirones including buspirone, gepirone, ipsapirone, revospirone, and tandospirone is 1-(2-pyrimidinyl)piperazine (1-PP). 1-PP possesses 5-HT1A partial agonist and α2-adrenergic antagonist actions and likely contributes overall mostly to side effects.

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

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Introduction

Amotivational syndrome is a chronic psychiatric disorder characterised by signs that are linked to cognitive and emotional states such as detachment, blunted emotion and drives, executive functions like memory and attention, disinterest, passivity, apathy, and a general lack of motivation. This syndrome can be branched into two subtypes – marijuana amotivational syndrome, interchangeably known as cannabis induced amotivational syndrome which is caused by usage and/or dependency of the substance and is primarily associated with long-term effects of cannabis use, and SSRI-induced amotivational syndrome or SSRI-induced apathy caused by the intake of SSRI medication dosage. According to the Handbook of Clinical Psychopharmacology for Therapists, amotivational syndrome is listed as a possible side effect of SSRIs in the treatment of clinical depression.

Refer to Avolition.

Signs and Symptoms

Amotivational syndrome has been suspected to affect the frontal cortex or frontal lobe of the brain by the impairment of that region which monitors cognitive functions and skills that revolve around emotional expression, decision making, prioritisation, and internal, purposeful mental action. It is most often detected through signs that are linked to apathy such as disinhibited presentations, short and long term memory deficit or amnesia, a lack of emotional display also known as emotional blunting, relative disinterest, passivity, and reluctance to participate in prolonged activities that require attention or tenacity. Common symptoms that may also be experienced include incoherence, an inability to concentrate on tasks, emotional distress, a diminished level of consciousness, selective attention or attentional control, and being withdrawn and asocial. These symptoms are also generally linked to cannabis consumption and abuse, as well as SSRI medication that are often used as forms of antidepressant medication.

Subtypes

Cannabis Amotivational Syndrome

The term amotivational syndrome was first devised to understand and explain the diminished drive and desire to work or compete among the population of youth who are frequent consumers of cannabis and has since been researched through various methodological studies with this focus on cannabis, or marijuana. Cannabis amotivational syndrome is often used interchangeably with marijuana amotivational syndrome and marijuana or cannabis induced or related amotivational syndrome. Cannabis related amotivational syndrome is closely tied with cannabis use disorder which is recognised in the fifth version of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) and has similar conditions such as withdrawing and giving up from daily activities and neglecting major roles and responsibilities. It is one of the major complications of chronic exposure to cannabis as it includes the effects and elements of cognitive deficit or cognitive impairment that are similar to what appears in schizophrenia and depression. It is characterised by a gradual detachment and disconnect from the outer world due to a loss of emotional reactivity, drives, and aims. Responsiveness to any stimuli is limited, and those affected are unable to experience or anticipate any pleasure except through the use of cannabis. Marijuana amotivational syndrome has been looked at within the context of how motivation-related constructs influence the young adult in the context of the school or workplace as those affected have poor levels of school-related functioning, are unable to focus on schoolwork due to their lack of motivation, are less satisfied with participating in educational activities, and easily enter into conflict with scholastic authorities. Additionally, marijuana amotivational syndrome is closely linked to self-efficacy, a psychological concept which encapsulates how one values their capabilities and the amount of confidence they hold in their capabilities to persevere – this is related to motivation as people who hold a high amount of self-efficacy are more likely to make efforts to complete a task and persist longer in those efforts compared to those with lower self-efficacy.

SSRI-Induced Amotivational Syndrome

Amotivational syndrome caused or related to SSRI dosage is also commonly known as apathy syndrome, SSRI-induced apathy syndrome, SSRI-induced apathy, and antidepressant apathy syndrome. “Apathy is defined as the presence of diminished motivation in an individual – a development that is not attributable to a reduced level of consciousness, cognitive impairment (e.g. dementia), or emotional distress (i.e. depression)”. This syndrome is linked to the consumption and dosage of selective serotonin reuptake inhibitors (SSRIs), which are typically used as antidepressants, and has been reported in patients undergoing SSRI treatment as SSRIs may modulate and alter the activity occurring in the frontal lobe of the brain, one of the four major lobes in the brain that contains most of the dopaminergic pathways that are associated with reward, attention, short-term memory tasks, planning, and motivation. This syndrome may be related to serotonergic effects on the frontal lobes and/or serotonergic modulation of mid-brain dopaminergic systems which project to the prefrontal cortex, both suggesting the possibility of frontal lobe dysfunction due to the alteration of serotonin levels. This brings on a number of similar symptoms that lead to dose dependency and apathy, however, it has often been unrecognized and undiagnosed due to the lack of prevalent data and its subtle and delayed onset.

When looking at SSRI-induced amotivational syndrome as a clinical side effect, it can be looked at through a behavioural perspective as well as an emotional perspective. When looked at as a behavioural syndrome the association between apathy or low motivation and SSRI prescription has been recognised as a potential side effect, for example, behavioural apathy has been noted in several case reports. Aside from a behavioural perspective, an emotional perspective emphasizes the emotional aspects of indifference such as a lack of emotional responsiveness, a reduction in emotional sensitivity such as numbing or blunting emotion, affected patients often describe having a restricted range of emotions including those emotions that are a part of everyday life, and distinct emotional themes in affected patience that include a general reduction in the intensity or experience of all emotions, both positive and negative, and feeling emotionally detached and “just not caring”, diminishing emotionality in both personal and professional interpersonal relationships.

Treatment and Evaluation

Cannabis Amotivational Syndrome

Treatment of cannabis amotivational syndrome is like the treatment for cannabis dependence in which there should be careful evaluation for any signs of depression that predate the development of the amotivational syndrome and may be the basis for cannabis dependence and usage. The user is slowly weaned off usage through urine monitoring, self-help groups, education, and therapy in different treatment settings such as group, family, and individual therapy in order to separate themselves from cannabis consumption and any cannabis-related environment as both contribute to the cognitive aspects of amotivational syndrome.

SSRI-Induced Amotivational Syndrome

Treatments include gradually reducing or discontinuing the SSRI, changing the SSRI to another antidepressant class, or co-prescribing with the SSRI a medication that boosts dopamine, such as the antidepressant bupropion.

Current Research and Discourse

Cannabis Amotivational Syndrome

Though there is a prevalent relationship between cannabis consumption and amotivational syndrome, there is still some considerable debate that exists around cannabis consumption causing amotivational syndrome meaning that it may not be a single entity but rather a collection of behaviours that form the result of a combination of effects of an already existent or reactive depression that occurs alongside cannabis’s ability to facilitate a unique attention state. Trait absorption is often mentioned within discourses surrounding cannabis-induced amotivational syndrome and it states that the traits associated with a large majority of marijuana users, which are similar to traits found in those who have amotivational syndrome, such as boredom and a general feeling of disconnect, are absorbed and taken up by the cannabis user. It is used as a common argument against cannabis potentially being able to cause amotivational syndrome, instead, many cannabis users have stated that users often absorb what is often thought of as the typical set of traits marijuana consumers possess, which overlap with some of the traits found in amotivational syndrome. As a result, many have proposed that rather than cannabis being thought of as a psychologically harmful substance, it is instead thought of as an active placebo in which its effects on the mind are placebo effects in response to minimal physiological action rather than being a direct cause of the psychological changes seen in users.

Additionally, though research has been conducted, it is recognized that there is not enough substantial empirical research to conclude that the use of cannabis leads to amotivational syndrome. Anecdotal information such as statements taken from cannabis users includes feeling listless and lethargic. Amotivational syndrome still ranks high among the key problems associated with the drug, with researchers having adopted the phrase “amotivational” to describe lethargic cannabis users. The US Department of Health and Human Services also warns that usage in youth may result in amotivational symptoms such as an apathetic approach to life, fatigue, and poor academic and work performance. However, empirical research on the effects of cannabis on users’ motivation implies that there is no strong correlation and that there are numerous alternative explanations of these negative outcomes as a review of laboratory performance research, education data, and employment statistics fail to offer consistent evidence that directly link cannabis to any symptoms associated with amotivational syndrome. Though several studies contain data in which heavy cannabis users have reported feeling a lack of motivation, it has also been acknowledged that other variables such as comorbid drug use and baselines for low motivation may not be examined.

SSRI-Induced Amotivational Syndrome

Most research in psychological fields regarding amotivational syndrome caused by SSRI treatment has revolved around case studies and anecdotal reports to understand how SSRI medication influences levels of motivation and apathy in patients. There is considerable overlap in the clinical presentations of apathy and motivation and depression. Many patients with amotivational or apathy syndrome reported that they felt a lack of motivation that was unlike what they had sometimes experienced during previous episodes or depression, or that their feelings of apathy had no link to depression. Apathy syndrome has also been reported in a number of patients that have received or are receiving SSRI treatment over the last decade, which has also been linked to a deficit in the performance and activities of daily living, signalling a functional decline. It is a common behavioural problem that often goes undiagnosed and untreated, which is why it is considered to be clinical significant. Neuropsychological research has shown that a common feature of amotivational syndrome involves the presence of lesions and other abnormalities in the circulation of the frontal lobe. Neuroimaging studies of clinical populations have also reported correlations between apathy and structural and functional changes in the frontal lobe in the anterior cingulate gyrus and subregions of the basal ganglia. Recent case-control studies have also reported that apathy has appeared to be greater in patients who were treated with SSRI medication compared to patients who were not. Current findings are consistent with other findings supporting the correlation of SSRI and apathy due to the occurrence of abnormalities found within various regions of the frontal lobe. Though amotivational syndrome has been an emerging concern for pharmacotherapeutic industries to consider, there is still a growing body of empirical investigations that need to continue in order for the development of novel therapeutic interventions to improve, as well as treatment. Currently, empirical studies are limited and there is not a substantial enough amount of research to fully understand the link between frontal lobe abnormalities caused by SSRIs and thus resulting in amotivational syndrome. There is a lack of large-scale clinical studies that focus on the prevalence of SSRI-induced amotivational syndrome with regards to emotional blunting and apathy in both psychiatric or primary care populations, despite the high prescription rates for SSRI medication. There are also no current clinically popular scales to measure and assess SSRI-induced apathy. The Oxford Questionnaire of Emotional Side Effects of Antidepressants (OQESA) is a scale under development and presents a 26-item, Likert-style, self-report scale that aims to understand respondents’ emotional experiences such as a general reduction in emotions, a reduction in positive emotions, emotional detachment and blunting, and feelings of not caring. Respondents are also asked to what extent they believe their antidepressant is responsible for these emotional symptoms.

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What is a Serotonin Releasing Agent?

Published on by Andrew Marshall3 Comments

Introduction

A serotonin releasing agent (SRA) is a type of drug that induces the release of serotonin into the neuronal synaptic cleft. A selective serotonin releasing agent (SSRA) is an SRA with less significant or no efficacy in producing neurotransmitter efflux at other types of monoamine neurons.

SSRAs have been used clinically as appetite suppressants, and they have also been proposed as novel antidepressants and anxiolytics with the potential for a faster onset of action and superior efficacy relative to the selective serotonin reuptake inhibitors (SSRIs).

A closely related type of drug is a serotonin reuptake inhibitor (SRI).

Examples and Use of SRAs

Amphetamines like MDMA, MDEA, MDA, and MBDB, among other relatives, are recreational drugs termed entactogens. They act as serotonin-norepinephrine-dopamine releasing agents (SNDRAs) and also agonise serotonin receptors such as those in the 5-HT2 subfamily. Fenfluramine, chlorphentermine, and aminorex, which are also amphetamines and relatives, were formerly used as appetite suppressants but were discontinued due to concerns of cardiac valvulopathy. This side effect has been attributed to their additional action of potent agonism of the 5-HT2B receptor. The designer drug 4-methylaminorex, which is an SNDRA and 5-HT2B agonist, has been reported to cause this effect as well.

Many tryptamines, such as DMT, DET, DPT, DiPT, psilocin, and bufotenin, are SRAs as well as non-selective serotonin receptor agonists. These drugs are serotonergic psychedelics, which is a consequence of their ability to activate the 5-HT2A receptor. αET and αMT, also tryptamines, are SNDRAs and non-selective serotonin receptor agonists that were originally thought to be monoamine oxidase inhibitors and were formerly used as antidepressants. They have since been discontinued and are now encountered solely as recreational drugs.

Indeloxazine is an SRA and norepinephrine reuptake inhibitor that was formerly used as an antidepressant, nootropic, and neuroprotective.

List of SSRAs

Pharmaceutical Drugs

  • Chlorphentermine (Apsedon, Desopimon, Lucofen)
  • Cloforex (Oberex) (prodrug of chlorphentermine)
  • Dexfenfluramine (Redux) (enantiomer of fenfluramine)
  • Etolorex (prodrug of chlorphentermine; never marketed)
  • Fenfluramine (Pondimin, Fen-Phen)
  • Flucetorex (related to chlorphentermine; never marketed)
  • Indeloxazine (Elen, Noin) (non-selective; discontinued)
  • Levofenfluramine (enantiomer of fenfluramine)
  • Carbamazepine (Equetro, Epitol, and many other variations)

Research Chemicals

  • Amiflamine (FLA-336)
  • Viqualine (PK-5078)
  • 2-Methyl-3,4-methylenedioxyamphetamine (2-Methyl-MDA)
  • 3-Methoxy-4-methylamphetamine (MMA)
  • 3-Methyl-4,5-methylenedioxyamphetamine (5-Methyl-MDA)
  • 3,4-Ethylenedioxy-N-methylamphetamine (EDMA)
  • 4-Methoxyamphetamine (PMA)
  • 4-Methoxy-N-ethylamphetamine (PMEA)
  • 4-Methoxy-N-methylamphetamine (PMMA)
  • 4-Methylthioamphetamine (4-MTA)
  • 5-(2-Aminopropyl)-2,3-dihydrobenzofuran (5-APDB)
  • 5-Indanyl-2-aminopropane (IAP)
  • 5-Methoxy-6-methylaminoindane (MMAI)
  • 5-Trifluoromethyl-2-aminoindane (TAI)
  • 5,6-Methylenedioxy-2-aminoindane (MDAI)
  • 5,6-Methylenedioxy-N-methyl-2-aminoindane (MDMAI)
  • 6-Chloro-2-aminotetralin (6-CAT)
  • 6-Tetralinyl-2-aminopropane (TAP)
  • 6,7-Methylenedioxy-2-aminotetralin (MDAT)
  • 6,7-Methylenedioxy-N-methyl-2-aminotetralin (MDMAT)
  • N-Ethyl-5-trifluoromethyl-2-aminoindane (ETAI)
  • 6-(2-aminopropil)benzofurans (6-APB)
  • 5-(2-aminopropyl)benzofuran (5-APB)

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What is a Serotonin Transporter?

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Introduction

The serotonin transporter (SERT or 5-HTT) also known as the sodium-dependent serotonin transporter and solute carrier family 6 menmber 4 is a protein that in humans is encoded by the SLC6A4 gene. SERT is a type of monoamine transporter protein that transports the neurotransmitter serotonin from the synaptic cleft back to the presynaptic neuron, in a process known as serotonin reuptake.

This transport of serotonin by the SERT protein terminates the action of serotonin and recycles it in a sodium-dependent manner. Many antidepressant medications of the SSRI and tricyclic antidepressant classes work by binding to SERT and thus reducing serotonin reuptake. It is a member of the sodium:neurotransmitter symporter family. A repeat length polymorphism in the promoter of this gene has been shown to affect the rate of serotonin uptake and may play a role in sudden infant death syndrome, aggressive behaviour in Alzheimer disease patients, post-traumatic stress disorder and depression-susceptibility in people experiencing emotional trauma.

Mechanism of Action

Serotonin-reuptake transporters are dependent on both the concentration of potassium ion in the cytoplasm and the concentrations of sodium and chloride ions in the extracellular fluid. In order to function properly the serotonin transporter requires the membrane potential created by the sodium-potassium adenosine triphosphatase.

The serotonin transporter first binds a sodium ion, followed by the serotonin, and then a chloride ion; it is then allowed, thanks to the membrane potential, to flip inside the cell freeing all the elements previously bound. Right after the release of the serotonin in the cytoplasm a potassium ion binds to the transporter which is now able to flip back out returning to its active state.

Function

The serotonin transporter removes serotonin from the synaptic cleft back into the synaptic boutons. Thus, it terminates the effects of serotonin and simultaneously enables its reuse by the presynaptic neuron.

Neurons communicate by using chemical messengers like serotonin between cells. The transporter protein, by recycling serotonin, regulates its concentration in a gap, or synapse, and thus its effects on a receiving neuron’s receptors.

Medical studies have shown that changes in serotonin transporter metabolism appear to be associated with many different phenomena, including alcoholism, clinical depression, obsessive–compulsive disorder (OCD), romantic love, hypertension and generalized social phobia.

The serotonin transporter is also present in platelets; there, serotonin functions as a vasoconstrictive substance. It also serves as a signalling molecule to induce platelet aggregation.

Pharmacology

In 1995 and 1996, scientists in Europe had identified the polymorphism 5-HTTLPR, a serotonin-transporter in the gene SLC6A4. In December 1996, a group of researchers led by D.A. Collier of the Institute of Psychiatry, Psychology and Neuroscience, published their findings in Molecular Psychiatry, that, “5-HTTLPR-dependent variation in functional 5-HTT expression is a potential genetic susceptibility factor for affective disorders.”

SERT spans the plasma membrane 12 times. It belongs to the NE, DA, SERT monoamine transporter family. Transporters are important sites for agents that treat psychiatric disorders. Drugs that reduce the binding of serotonin to transporters (serotonin reuptake inhibitors, or SRIs) are used to treat mental disorders. The selective serotonin reuptake inhibitor (SSRI) fluoxetine and the tricyclic antidepressant (TCA) clomipramine are examples of serotonin reuptake inhibitors.

Following the elucidation of structures of the homologous bacterial transporter, LeuT, co-crystallised with tricyclic antidepressants in the vestibule leading from the extracellular space to the central substrate site it was inferred that this binding site did also represent the binding site relevant for antidepressant binding in SERT. However, studies on SERT showed that tricyclic antidepressants and selective serotonin reuptake inhibitors bind to the central binding site overlapping the substrate binding site. The Drosophila dopamine transporter, which displays a pharmacology similar to SERT, was crystallised with tricyclic antidepressants and confirmed the earlier finding that the substrate binding site is also the antidepressant binding site.

Ligands

  • DASB, also known as 3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile, is a compound that binds to the serotonin transporter.
  • compound 4b: Ki = 17 pM; 710-fold and 11,100-fold selective over DAT and NET
  • compound (+)-12a: Ki = 180 pM at hSERT; >1000-fold selective over hDAT, hNET, 5-HT1A, and 5-HT6. Isosteres
  • 3-cis-(3-Aminocyclopentyl)indole 8a: Ki = 220 pM
  • allosteric modulator: 3′-Methoxy-8-methyl-spiro{8-azabicyclo[3.2.1]octane-3,5′(4′H)-isoxazole} (compound 7a)
  • allosteric modulator: p-Trifluoromethyl-methcathinone

Genetics

The gene that encodes the serotonin transporter is called solute carrier family 6 (neurotransmitter transporter, serotonin), member 4 (SLC6A4, refer to Solute carrier family). In humans the gene is found on chromosome 17 on location 17q11.1–q12.

Mutations associated with the gene may result in changes in serotonin transporter function, and experiments with mice have identified more than 50 different phenotypic changes as a result of genetic variation. These phenotypic changes may, e.g., be increased anxiety and gut dysfunction. Some of the human genetic variations associated with the gene are:

  • Length variation in the serotonin-transporter-gene-linked polymorphic region (5-HTTLPR)
  • rs25531 — a single nucleotide polymorphism (SNP) in the 5-HTTLPR
  • rs25532 — another SNP in the 5-HTTLPR
  • STin2 — a variable number of tandem repeats (VNTR) in the functional intron 2
  • G56A on the second exon
  • I425V on the ninth exon

Length Variation in 5-HTTLPR

Refer to 5-HTTLPR.

According to a 1996 article in The Journal of Neurochemistry, the promoter region of the SLC6A4 gene contains a polymorphism with “short” and “long” repeats in a region: 5-HTT-linked polymorphic region (5-HTTLPR or SERTPR). The short variation has 14 repeats of a sequence while the long variation has 16 repeats. A second 1996 article stated that the short variation leads to less transcription for SLC6A4, and it has been found that it can partly account for anxiety-related personality traits. This polymorphism has been extensively investigated in over 300 scientific studies (as of 2006). The 5-HTTLPR polymorphism may be subdivided further: One study published in 2000 found 14 allelic variants (14-A, 14-B, 14-C, 14-D, 15, 16-A, 16-B, 16-C, 16-D, 16-E, 16-F, 19, 20 and 22) in a group of around 200 Japanese and Caucasian people.

In addition to altering the expression of SERT protein and concentrations of extracellular serotonin in the brain, the 5-HTTLPR variation is associated with changes in brain structure. One 2005 study found less grey matter in perigenual anterior cingulate cortex and amygdala for short allele carriers of the 5-HTTLPR polymorphism compared to subjects with the long/long genotype.

In contrast, a 2008 meta-analysis found no significant overall association between the 5-HTTLPR polymorphism and autism. A hypothesized gene–environment interaction between the short/short allele of the 5-HTTLPR and life stress as predictor for major depression has suffered a similar fate: after an influential initial report in 2003 there were mixed results in replication in 2008, and a 2009 meta-analysis was negative.

rs25532

rs25532 is a SNP (C>T) close to the site of 5-HTTLPR. It has been examined in connection with obsessive compulsive disorder (OCD).

I425V

I425V is a rare mutation on the ninth exon. In 2003, researchers from Japan and the US reported that they had found this genetic variation in unrelated families with OCD, and have found that it leads to faulty transporter function and regulation. A second variant in the same gene of some patients with this mutation suggests a genetic “double hit”, resulting in greater biochemical effects and more severe symptoms.

VNTR in STin2

Another noncoding polymorphism is a VNTR in the second intron (STin2). In a 2005 study, it was found with three alleles: 9, 10 and 12 repeats. A meta-analysis has found that the 12 repeat allele of the STin2 VNTR polymorphism had some minor (with odds ratio 1.24), but statistically significant, association with schizophrenia. A 2008 meta-analysis found no significant overall association between the STin2 VNTR polymorphism and autism. Furthermore, a 2003 meta-analysis of affective disorders, major depressive disorder and bipolar disorder, found a minor association to the intron 2 VNTR polymorphism, but the results of the meta-analysis were dependent upon a large effect from one individual study.

The polymorphism has also been related to personality traits with a 2008 Russian study finding individuals with the STin2.10 allele having lower neuroticism scores as measured with the Eysenck Personality Inventory.

Neuroimaging

The distribution of the serotonin transporter in the brain may be imaged with positron emission tomography using radioligands called DASB and DAPP; the first such studies on the human brain were reported in 2000. DASB and DAPP are not the only radioligands for the serotonin transporter. There are numerous others, with the most popular probably being the β-CIT radioligand with an iodine-123 isotope that is used for brain scanning with single-photon emission computed tomography (SPECT) according to a 1993 article in the Journal of Neural Transmission. The radioligands were used in 2006 to examine whether variables such as age, gender or genotype are associated with differential serotonin transporter binding. Healthy subjects that have a high score of neuroticism—a personality trait in the Revised NEO Personality Inventory—were found to have more serotonin transporter binding in the thalamus in 2007.

Neuroimaging and Genetics

Studies on the serotonin transporter have combined neuroimaging and genetics methods, e.g., a voxel-based morphometry study found less grey matter in perigenual anterior cingulate cortex and amygdala for short allele carriers of the 5-HTTLPR polymorphism compared to subjects with the long/long genotype.

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What is Isocarboxazid?

Published on by Andrew Marshall1 Comment

Introduction

Isocarboxazid (Marplan, Marplon, Enerzer) is a non-selective, irreversible monoamine oxidase inhibitor (MAOI) of the hydrazine class used as an antidepressant.

Outline

Along with phenelzine and tranylcypromine, it is one of only three classical MAOIs still available for clinical use in the treatment of psychiatric disorders in the United States, though it is not as commonly employed in comparison to the others.

Isocarboxazid is primarily used to treat mood and anxiety disorders. It has also been investigated in the treatment of schizophrenia, Parkinson’s disease and other dementia-related disorders.

Isocarboxazid, as well as other MAOIs, increase the levels of the monoamine neurotransmitters serotonin, dopamine, norepinephrine, epinephrine, melatonin, phenethylamine in the brain.

Classical MAOIs, including isocarboxazid, are used only rarely due to prominent food and drug interactions and have been largely superseded by newer antidepressants such as the selective serotonin reuptake inhibitors (SSRIs). The cause of the interactions is because MAOIs inhibit the metabolism of dietary amines (e.g., tyramine) and the monoamine neurotransmitters. In combination with other drugs that increase the levels of the monoamine neurotransmitters such as the SSRIs, or with certain foods high in dietary amines such as aged cheeses, MAOIs can produce dangerous elevations of monoamine neurotransmitters resulting in potentially life-threatening syndromes such as hypertensive crisis and serotonin syndrome.

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

Published on by Andrew Marshall8 Comments

Introduction

Sertraline, sold under the brand name Zoloft among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class.

The efficacy of sertraline for depression is similar to that of other antidepressants, and the differences are mostly confined to side effects. Sertraline is better tolerated than the older tricyclic antidepressants, and it may work better than fluoxetine for some subtypes of depression. Sertraline is effective for panic disorder, social anxiety disorder, generalised anxiety disorder (GAD), and obsessive-compulsive disorder (OCD). However, for OCD, cognitive behavioural therapy (CBT), particularly in combination with sertraline, is a better treatment. Although approved for post-traumatic stress disorder, sertraline leads to only modest improvement in this condition. Sertraline also alleviates the symptoms of premenstrual dysphoric disorder and can be used in sub-therapeutic doses or intermittently for its treatment.

Sertraline shares the common side effects and contraindications of other SSRIs, with high rates of nausea, diarrhoea, insomnia, and sexual side effects, but it appears not to lead to much weight gain, and its effects on cognitive performance are mild. Similar to other antidepressants, the use of sertraline for depression may be associated with a higher rate of suicidal thoughts and behaviour in people under the age of 25. It should not be used together with MAO inhibitor medication: this combination causes serotonin syndrome. Sertraline taken during pregnancy is associated with a significant increase in congenital heart defects in newborns.

Sertraline was invented and developed by scientists at Pfizer and approved for medical use in the United States in 1991. It is on the World Health Organisation’s List of Essential Medicines. It is available as a generic medication. In 2016, sertraline was the most commonly prescribed psychiatric medication in the US and in 2019, it was the twelfth most commonly prescribed medication in the US, with over 37 million prescriptions.

Brief History

The history of sertraline dates back to the early 1970s, when Pfizer chemist Reinhard Sarges invented a novel series of psychoactive compounds, including lometraline, based on the structures of the neuroleptics thiothixene and pinoxepin. Further work on these compounds led to tametraline, a norepinephrine and weaker dopamine reuptake inhibitor. Development of tametraline was soon stopped because of undesired stimulant effects observed in animals. A few years later, in 1977, pharmacologist Kenneth Koe, after comparing the structural features of a variety of reuptake inhibitors, became interested in the tametraline series. He asked another Pfizer chemist, Willard Welch, to synthesize some previously unexplored tametraline derivatives. Welch generated a number of potent norepinephrine and triple reuptake inhibitors, but to the surprise of the scientists, one representative of the generally inactive cis-analogues was a serotonin reuptake inhibitor. Welch then prepared stereoisomers of this compound, which were tested in vivo by animal behavioural scientist Albert Weissman. The most potent and selective (+)-isomer was taken into further development and eventually named sertraline. Weissman and Koe recalled that the group did not set up to produce an antidepressant of the SSRI type – in that sense their inquiry was not “very goal driven”, and the discovery of the sertraline molecule was serendipitous. According to Welch, they worked outside the mainstream at Pfizer, and even “did not have a formal project team”. The group had to overcome initial bureaucratic reluctance to pursue sertraline development, as Pfizer was considering licensing an antidepressant candidate from another company.

Sertraline was approved by the US Food and Drug Administration (FDA) in 1991 based on the recommendation of the Psychopharmacological Drugs Advisory Committee; it had already become available in the United Kingdom the previous year. The FDA committee achieved a consensus that sertraline was safe and effective for the treatment of major depression. During the discussion, Paul Leber, the director of the FDA Division of Neuropharmacological Drug Products, noted that granting approval was a “tough decision”, since the treatment effect on outpatients with depression had been “modest to minimal”. Other experts emphasized that the drug’s effect on inpatients had not differed from placebo and criticised poor design of the clinical trials by Pfizer. For example, 40% of participants dropped out of the trials, significantly decreasing their validity.

Until 2002, sertraline was only approved for use in adults ages 18 and over; that year, it was approved by the FDA for use in treating children aged 6 or older with severe OCD. In 2003, the UK Medicines and Healthcare products Regulatory Agency issued a guidance that, apart from fluoxetine (Prozac), SSRIs are not suitable for the treatment of depression in patients under 18. However, sertraline can still be used in the UK for the treatment of OCD in children and adolescents. In 2005, the FDA added a boxed warning concerning paediatric suicidal behaviour to all antidepressants, including sertraline. In 2007, labelling was again changed to add a warning regarding suicidal behaviour in young adults ages 18 to 24.

Medical Uses

Sertraline has been approved for major depressive disorder (MDD), obsessive-compulsive disorder (OCD), posttraumatic stress disorder (PTSD), premenstrual dysphoric disorder (PMDD), panic disorder, and social anxiety disorder (SAD). Sertraline is not approved for use in children except for those with OCD.

Depression

Multiple controlled clinical trials established efficacy of sertraline for the treatment of depression. Sertraline is also an effective antidepressant in the routine clinical practice. Continued treatment with sertraline prevents both a relapse of the current depressive episode and future episodes (recurrence of depression).

In several double-blind studies, sertraline was consistently more effective than placebo for dysthymia, a more chronic variety of depression, and comparable to imipramine in that respect. Sertraline also improves the depression of dysthymic patients to a greater degree than psychotherapy.

Limited paediatric data also demonstrates reduction in depressive symptoms in the paediatric population though remains a second line therapy after fluoxetine.

Comparison with Other Antidepressants

In general, sertraline efficacy is similar to that of other antidepressants. For example, a meta-analysis of 12 new-generation antidepressants showed that sertraline and escitalopram are the best in terms of efficacy and acceptability in the acute-phase treatment of adults with depression. Comparative clinical trials demonstrated that sertraline is similar in efficacy against depression to moclobemide, nefazodone, escitalopram, bupropion, citalopram, fluvoxamine, paroxetine, venlafaxine, and mirtazapine. Sertraline may be more efficacious for the treatment of depression in the acute phase (first 4 weeks) than fluoxetine.

There are differences between sertraline and some other antidepressants in their efficacy in the treatment of different subtypes of depression and in their adverse effects. For severe depression, sertraline is as good as clomipramine but is better tolerated. Sertraline appears to work better in melancholic depression than fluoxetine, paroxetine, and mianserin and is similar to the tricyclic antidepressants such as amitriptyline and clomipramine. In the treatment of depression accompanied by OCD, sertraline performs significantly better than desipramine on the measures of both OCD and depression. Sertraline is equivalent to imipramine for the treatment of depression with co-morbid panic disorder, but it is better tolerated. Compared with amitriptyline, sertraline offered a greater overall improvement in quality of life of depressed patients.

Depression in Elderly

Sertraline used for the treatment of depression in elderly (older than 60) patients is superior to placebo and comparable to another SSRI fluoxetine, and tricyclic antidepressants (TCAs) amitriptyline, nortriptyline and imipramine. Sertraline has much lower rates of adverse effects than these TCAs, with the exception of nausea, which occurs more frequently with sertraline. In addition, sertraline appears to be more effective than fluoxetine or nortriptyline in the older-than-70 subgroup. Accordingly, a meta-analysis of antidepressants in older adults found that sertraline, paroxetine and duloxetine were better than placebo. On the other hand, in a 2003 trial the effect size was modest, and there was no improvement in quality of life as compared to placebo. With depression in dementia, there is no benefit of sertraline treatment compared to either placebo or mirtazapine.

Obsessive-Compulsive Disorder

Sertraline is effective for the treatment of OCD in adults and children. It was better tolerated and, based on intention-to-treat analysis, performed better than the gold standard of OCD treatment clomipramine. Continuing sertraline treatment helps prevent relapses of OCD with long-term data supporting its use for up to 24 months. It is generally accepted that the sertraline dosages necessary for the effective treatment of OCD are higher than the usual dosage for depression. The onset of action is also slower for OCD than for depression. The treatment recommendation is to start treatment with a half of maximal recommended dose for at least two months. After that, the dose can be raised to the maximal recommended in the cases of unsatisfactory response.

CBT alone was superior to sertraline in both adults and children; however, the best results were achieved using a combination of these treatments.

Panic Disorder

Sertraline is superior to placebo for the treatment of panic disorder. The response rate was independent of the dose. In addition to decreasing the frequency of panic attacks by about 80% (vs. 45% for placebo) and decreasing general anxiety, sertraline resulted in improvement of quality of life on most parameters. The patients rated as “improved” on sertraline reported better quality of life than the ones who “improved” on placebo. The authors of the study argued that the improvement achieved with sertraline is different and of a better quality than the improvement achieved with placebo. Sertraline is equally effective for men and women, and for patients with or without agoraphobia. Previous unsuccessful treatment with benzodiazepines does not diminish its efficacy. However, the response rate was lower for the patients with more severe panic. Starting treatment simultaneously with sertraline and clonazepam, with subsequent gradual discontinuation of clonazepam, may accelerate the response.

Double-blind comparative studies found sertraline to have the same effect on panic disorder as paroxetine or imipramine. While imprecise, comparison of the results of trials of sertraline with separate trials of other anti-panic agents (clomipramine, imipramine, clonazepam, alprazolam, and fluvoxamine) indicates approximate equivalence of these medications.

Other Anxiety Disorders

Sertraline has been successfully used for the treatment of social anxiety disorder. All three major domains of the disorder (fear, avoidance, and physiological symptoms) respond to sertraline. Maintenance treatment, after the response is achieved, prevents the return of the symptoms. The improvement is greater among the patients with later, adult onset of the disorder. In a comparison trial, sertraline was superior to exposure therapy, but patients treated with the psychological intervention continued to improve during a year-long follow-up, while those treated with sertraline deteriorated after treatment termination. The combination of sertraline and CBT appears to be more effective in children and young people than either treatment alone.

Sertraline has not been approved for the treatment of generalised anxiety disorder; however, several guidelines recommend it as a first-line medication referring to good quality controlled clinical trials.

Premenstrual Dysphoric Disorder

Sertraline is effective in alleviating the symptoms of premenstrual dysphoric disorder (PMDD), a severe form of premenstrual syndrome. Significant improvement was observed in 50-60% of cases treated with sertraline vs. 20-30% of cases on placebo. The improvement began during the first week of treatment, and in addition to mood, irritability, and anxiety, improvement was reflected in better family functioning, social activity and general quality of life. Work functioning and physical symptoms, such as swelling, bloating and breast tenderness, were less responsive to sertraline. Taking sertraline only during the luteal phase, that is, the 12-14 days before menses, was shown to work as well as continuous treatment. Continuous treatment with sub-therapeutic doses of sertraline (25 mg vs. usual 50-100 mg) is also effective.

Other Indications

Sertraline is approved for the treatment of post-traumatic stress disorder (PTSD). National Institute of Clinical Excellence recommends it for patients who prefer drug treatment to a psychological one. Other guidelines also suggest sertraline as a first-line option for pharmacological therapy. When necessary, long-term pharmacotherapy can be beneficial. There are both negative and positive clinical trial results for sertraline, which may be explained by the types of psychological traumas, symptoms, and comorbidities included in the various studies. Positive results were obtained in trials that included predominantly women (75%) with a majority (60%) having physical or sexual assault as the traumatic event. Contrary to the above suggestions, a meta-analysis of sertraline clinical trials for PTSD found it to be not significantly better than placebo. Another meta-analysis relegated sertraline to the second line, proposing trauma focused psychotherapy as a first-line intervention. The authors noted that Pfizer had declined to submit the results of a negative trial for the inclusion into the meta-analysis making the results unreliable.

Sertraline when taken daily can be useful for the treatment of premature ejaculation. A disadvantage of sertraline is that it requires continuous daily treatment to delay ejaculation significantly.

A 2019 systematic review suggested that sertraline may be a good way to control anger, irritability and hostility in depressed patients and patients with other comorbidities.

Contraindications

Sertraline is contraindicated in individuals taking monoamine oxidase inhibitors or the antipsychotic pimozide. Sertraline concentrate contains alcohol and is therefore contraindicated with disulfiram. The prescribing information recommends that treatment of the elderly and patients with liver impairment “must be approached with caution”. Due to the slower elimination of sertraline in these groups, their exposure to sertraline may be as high as three times the average exposure for the same dose.

Side Effects

Nausea, ejaculation failure, insomnia, diarrhoea, dry mouth, somnolence, dizziness, tremor, headache, excessive sweating, fatigue, and decreased libido are the common adverse effects associated with sertraline with the greatest difference from placebo. Those that most often resulted in interruption of the treatment are nausea, diarrhoea and insomnia. The incidence of diarrhoea is higher with sertraline – especially when prescribed at higher doses – in comparison with other SSRIs.

Over more than six months of sertraline therapy for depression, people showed a nonsignificant weight increase of 0.1%. Similarly, a 30-month-long treatment with sertraline for OCD resulted in a mean weight gain of 1.5% (1 kg). Although the difference did not reach statistical significance, the average weight gain was lower for fluoxetine (1%) but higher for citalopram, fluvoxamine and paroxetine (2.5%). Of the sertraline group, 4.5% gained a large amount of weight (defined as more than 7% gain). This result compares favourably with placebo, where, according to the literature, 3-6% of patients gained more than 7% of their initial weight. The large weight gain was observed only among female members of the sertraline group; the significance of this finding is unclear because of the small size of the group.

Over a two-week treatment of healthy volunteers, sertraline slightly improved verbal fluency but did not affect word learning, short-term memory, vigilance, flicker fusion time, choice reaction time, memory span, or psychomotor coordination. In spite of lower subjective rating, that is, feeling that they performed worse, no clinically relevant differences were observed in the objective cognitive performance in a group of people treated for depression with sertraline for 1.5 years as compared to healthy controls. In children and adolescents taking sertraline for six weeks for anxiety disorders, 18 out of 20 measures of memory, attention and alertness stayed unchanged. Divided attention was improved and verbal memory under interference conditions decreased marginally. Because of the large number of measures taken, it is possible that these changes were still due to chance. The unique effect of sertraline on dopaminergic neurotransmission may be related to these effects on cognition and vigilance.

Sertraline has a low level of exposure of an infant through the breast milk and is recommended as the preferred option for the antidepressant therapy of breast-feeding mothers. There is 29-42% increase in congenital heart defects among children whose mothers were prescribed sertraline during pregnancy, with sertraline use in the first trimester associated with 2.7-fold increase in septal heart defects.

Abrupt interruption of sertraline treatment may result in withdrawal or discontinuation syndrome. Dizziness, insomnia, anxiety, agitation, and irritability are its common symptoms. It typically occurs within a few days from drug discontinuation and lasts a few weeks. The withdrawal symptoms for sertraline are less severe and frequent than for paroxetine, and more frequent than for fluoxetine. In most cases symptoms are mild, short-lived, and resolve without treatment. More severe cases are often successfully treated by temporary reintroduction of the drug with a slower tapering off rate.

Sertraline and SSRI antidepressants in general may be associated with bruxism and other movement disorders. Sertraline appears to be associated with microscopic colitis, a rare condition of unknown aetiology.

Sexual

Like other SSRIs, sertraline is associated with sexual side effects, including sexual arousal disorder, erectile dysfunction and difficulty achieving orgasm. While nefazodone and bupropion do not have negative effects on sexual functioning, 67% of men on sertraline experienced ejaculation difficulties versus 18% before the treatment. Sexual arousal disorder, defined as “inadequate lubrication and swelling for women and erectile difficulties for men”, occurred in 12% of people on sertraline as compared with 1% of patients on placebo. The mood improvement resulting from the treatment with sertraline sometimes counteracted these side effects, so that sexual desire and overall satisfaction with sex stayed the same as before the sertraline treatment. However, under the action of placebo the desire and satisfaction slightly improved. Some people continue experiencing sexual side effects after they stop taking SSRIs.

Suicide

The US Food and Drug Administration (FDA) requires all antidepressants, including sertraline, to carry a boxed warning stating that antidepressants increase the risk of suicide in persons younger than 25 years. This warning is based on statistical analyses conducted by two independent groups of FDA experts that found a 100% increase of suicidal thoughts and behaviour in children and adolescents, and a 50% increase – in the 18-24 age group.

Suicidal ideation and behaviour in clinical trials are rare. For the above analysis, the FDA combined the results of 295 trials of 11 antidepressants for psychiatric indications in order to obtain statistically significant results. Considered separately, sertraline use in adults decreased the odds of suicidal behaviour with a marginal statistical significance by 37% or 50% depending on the statistical technique used. The authors of the FDA analysis note that “given the large number of comparisons made in this review, chance is a very plausible explanation for this difference”. The more complete data submitted later by the sertraline manufacturer Pfizer indicated increased suicidal behaviour. Similarly, the analysis conducted by the UK Medicines and Healthcare Products Regulatory Agency (MHRA) found a 50% increase of odds of suicide-related events, not reaching statistical significance, in the patients on sertraline as compared to the ones on placebo.

Overdose

Acute overdosage is often manifested by emesis, lethargy, ataxia, tachycardia and seizures. Plasma, serum or blood concentrations of sertraline and norsertraline, its major active metabolite, may be measured to confirm a diagnosis of poisoning in hospitalised patients or to aid in the medicolegal investigation of fatalities. As with most other SSRIs its toxicity in overdose is considered relatively low.

Interactions

As with other SSRIs, sertraline may increase the risk of bleeding with NSAIDs (non-steroidal anti-inflammatory drugs such as ibuprofen, naproxen, mefenamic acid), antiplatelet drugs, anticoagulants, omega-3 fatty acids, vitamin E, and garlic supplements due to sertraline’s inhibitory effects on platelet aggregation via blocking serotonin transporters on platelets. Sertraline, in particular, may potentially diminish the efficacy of levothyroxine.

Sertraline is a moderate inhibitor of CYP2D6 and CYP2B6 in vitro. Accordingly, in human trials it caused increased blood levels of CYP2D6 substrates such as metoprolol, dextromethorphan, desipramine, imipramine and nortriptyline, as well as the CYP3A4/CYP2D6 substrate haloperidol. This effect is dose-dependent; for example, co-administration with 50 mg of sertraline resulted in 20% greater exposure to desipramine, while 150 mg of sertraline led to a 70% increase. In a placebo-controlled study, the concomitant administration of sertraline and methadone caused a 40% increase in blood levels of the latter, which is primarily metabolized by CYP2B6.

Sertraline had a slight inhibitory effect on the metabolism of diazepam, tolbutamide and warfarin, which are CYP2C9 or CYP2C19 substrates; the clinical relevance of this effect was unclear. As expected from in vitro data, sertraline did not alter the human metabolism of the CYP3A4 substrates erythromycin, alprazolam, carbamazepine, clonazepam, and terfenadine; neither did it affect metabolism of the CYP1A2 substrate clozapine.

Sertraline had no effect on the actions of digoxin and atenolol, which are not metabolised in the liver. Case reports suggest that taking sertraline with phenytoin or zolpidem may induce sertraline metabolism and decrease its efficacy, and that taking sertraline with lamotrigine may increase the blood level of lamotrigine, possibly by inhibition of glucuronidation.

CYP2C19 inhibitor esomeprazole increased sertraline concentrations in blood plasma by approximately 40%.

Clinical reports indicate that interaction between sertraline and the MAOIs isocarboxazid and tranylcypromine may cause serotonin syndrome. In a placebo-controlled study in which sertraline was co-administered with lithium, 35% of the subjects experienced tremors, while none of those taking placebo did.

Sertraline may interact with grapefruit juice.

Pharmacology

Pharmacodynamics

Sertraline is a selective serotonin reuptake inhibitor (SSRI). By binding serotonin transporter (SERT) it inhibits neuronal reuptake of serotonin and potentiates serotonergic activity in the central nervous system. Over time, this leads to a downregulation of pre-synaptic 5-HT1A receptors, which is associated with an improvement in passive stress tolerance, and delayed downstream increase in expression of brain-derived neurotrophic factor (BDNF), which may contribute to a reduction in negative affective biases. It does not significantly affect norepinephrine transporter (NET), serotonin, dopamine, adrenergic, histamine, acetylcholine, GABA or benzodiazepine receptors.

Sertraline also shows relatively high activity as an inhibitor of the dopamine transporter (DAT) and antagonist of the sigma σ1 receptor (but not the σ2 receptor). However, sertraline affinity for its main target (SERT) is much greater than its affinity for σ1 receptor and DAT. Although there could be a role for the σ1 receptor in the pharmacology of sertraline, the significance of this receptor in its actions is unclear. Similarly, the clinical relevance of sertraline’s blockade of the dopamine transporter is uncertain.

Pharmacokinetics

Absorption

Following a single oral dose of sertraline, mean peak blood levels of sertraline occur between 4.5 and 8.4 hours. Bioavailability is likely linear and dose-proportional over a dose range of 150 to 200 mg. Concomitant intake of sertraline with food slightly increases sertraline peak levels and total exposure. There is an approximate 2-fold accumulation of sertraline with continuous administration and steady-state levels are reached within one week.

Distribution

Sertraline is highly plasma protein bound (98.5%) across a concentration range of 20 to 500 ng/mL. Despite the high plasma protein binding, sertraline and its metabolite desmethylsertraline at respective tested concentrations of 300 ng/mL and 200 ng/mL were found not to interfere with the plasma protein binding of warfarin and propranolol, two other highly plasma protein-bound drugs.

Metabolism

Sertraline is subject to extensive first-pass metabolism, as indicated by a small study of radiolabelled sertraline in which less than 5% of plasma radioactivity was unchanged sertraline in two males. The principal metabolic pathway for sertraline is N-demethylation into desmethylsertraline (N-desmethylsertraline) mainly by CYP2B6. Reduction, hydroxylation, and glucuronide conjugation of both sertraline and desmethylsertraline also occur. Desmethylsertraline, while pharmacologically active, is substantially (50-fold) weaker than sertraline as a serotonin reuptake inhibitor and its influence on the clinical effects of sertraline is thought to be negligible. Based on in vitro studies, sertraline is metabolized by multiple cytochrome 450 isoforms; however, it appears that in the human body CYP2C19 plays the most important role, followed by CYP2B6. In addition to the cytochrome P450 system, sertraline can be oxidatively deaminated in vitro by monoamine oxidases; however, this metabolic pathway has never been studied in vivo.

Elimination

The elimination half-life of sertraline is on average 26 hours, with a range of 13 to 45 hours. The half-life of sertraline is longer in women (32 hours) than in men (22 hours), which leads to 1.5-fold higher exposure to sertraline in women compared to men. The elimination half-life of desmethylsertraline is 62 to 104 hours.

In a small study of two males, sertraline was excreted to similar degrees in urine and faeces (40 to 45% each within 9 days). Unchanged sertraline was not detectable in urine, whereas 12 to 14% unchanged sertraline was present in faeces.

Pharmacogenomics

CYP2C19 and CYP2B6 are thought to be the key cytochrome P450 enzymes involved in the metabolism of sertraline. Relative to CYP2C19 normal (extensive) metabolisers, poor metabolisers have 2.7-fold higher levels of sertraline and intermediate metabolisers have 1.4-fold higher levels. In contrast, CYP2B6 poor metabolisers have 1.6-fold higher levels of sertraline and intermediate metabolisers have 1.2-fold higher levels.

Society and Culture

Generic Availability

The US patent for Zoloft expired in 2006, and sertraline is available in generic form and is marketed under many brand names worldwide.

In May 2020, the FDA placed Zoloft on the list of drugs currently facing a shortage.

Other Uses

Lass-Flörl et al., 2003 finds sertraline significantly inhibits phospholipase B in the fungal genus Candida, reducing virulence. It is also a very effective leishmanicide. Specifically, Palit & Ali 2008 find that sertraline kills almost all promastigotes of Leishmania donovani.

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What is Citalopram?

Published on by Andrew Marshall13 Comments

Introduction

Citalopram, sold under the brand name Celexa among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class.

It is used to treat major depressive disorder, obsessive compulsive disorder, panic disorder, and social phobia. The antidepressant effects may take one to four weeks to occur. It is taken by mouth.

Common side effects include nausea, trouble sleeping, sexual problems, shakiness, feeling tired, and sweating. Serious side effects include an increased risk of suicide in those under the age of 25, serotonin syndrome, glaucoma, and QT prolongation. It should not be used in persons who take or have recently taken a MAO inhibitor. Antidepressant discontinuation syndrome may occur when stopped. There are concerns that use during pregnancy may harm the foetus.

Citalopram was approved for medical use in the United States in 1998. It is on the World Health Organisation’s List of Essential Medicines. It is available as a generic medication. In 2019, it was the 30th most commonly prescribed medication in the United States, with more than 21 million prescriptions.

Brief History

Citalopram was first synthesized in 1972 by chemist Klaus Bøgesø and his research group at the pharmaceutical company Lundbeck and was first marketed in 1989 in Denmark. It was first marketed in the US in 1998. The original patent expired in 2003, allowing other companies to legally produce and market generic versions.

Medical Uses

Depression

In the United States, citalopram is approved to treat major depressive disorder. Citalopram appears to have comparable efficacy and superior tolerability relative to other antidepressants. In the National Institute for Health and Clinical Excellence ranking of ten antidepressants for efficacy and cost-effectiveness, citalopram is fifth in effectiveness (after mirtazapine, escitalopram, venlafaxine, and sertraline) and fourth in cost-effectiveness. The ranking results were based on a 2009 meta-analysis by Andrea Cipriani; an update of the analysis in 2018 produced broadly similar results.

Evidence for effectiveness of citalopram for treating depression in children is uncertain.

Panic Disorder

Citalopram is licensed in the UK and other European countries for panic disorder, with or without agoraphobia.

Other

Citalopram may be used off-label to treat anxiety, and dysthymia, premenstrual dysphoric disorder, body dysmorphic disorder, and obsessive-compulsive disorder (OCD).

It appears to be as effective as fluvoxamine and paroxetine in OCD. Some data suggest the effectiveness of intravenous infusion of citalopram in resistant OCD. Citalopram is well tolerated and as effective as moclobemide in social anxiety disorder. There are studies suggesting that citalopram can be useful in reducing aggressive and impulsive behaviour. It appears to be superior to placebo for behavioural disturbances associated with dementia. It has also been used successfully for hypersexuality in early Alzheimer’s disease.

A meta-analysis, including studies with fluoxetine, paroxetine, sertraline, escitalopram, and citalopram versus placebo, showed SSRIs to be effective in reducing symptoms of premenstrual syndrome, whether taken continuously or just in the luteal phase. For alcoholism, citalopram has produced a modest reduction in alcoholic drink intake and increase in drink-free days in studies of alcoholics, possibly by decreasing desire or reducing the reward.

While on its own citalopram is less effective than amitriptyline in the prevention of migraines, in refractory cases, combination therapy may be more effective.

Citalopram and other SSRIs can be used to treat hot flashes.

A 2009 multisite randomised controlled study found no benefit and some adverse effects in autistic children from citalopram, raising doubts whether SSRIs are effective for treating repetitive behaviour in children with autism.

Some research suggests citalopram interacts with cannabinoid protein-couplings in the rat brain, and this is put forward as a potential cause of some of the drug’s antidepressant effect.

Administration

Citalopram is typically taken in one dose, either in the morning or evening. It can be taken with or without food. Its absorption does not increase when taken with food, but doing so can help prevent nausea. Nausea is often caused when the 5HT3 receptors actively absorb free serotonin, as this receptor is present within the digestive tract. The 5HT3 receptors stimulate vomiting. This side effect, if present, should subside as the body adjusts to the medication.

Citalopram is considered safe and well tolerated in the therapeutic dose range. Distinct from some other agents in its class, it exhibits linear pharmacokinetics and minimal drug interaction potential, making it a better choice for the elderly or comorbid patients.

Adverse Effects

Sexual dysfunction is often a side effect with SSRIs.

Citalopram theoretically causes side effects by increasing the concentration of serotonin in other parts of the body (e.g. the intestines). Other side effects, such as increased apathy and emotional flattening, may be caused by the decrease in dopamine release associated with increased serotonin. Citalopram is also a mild antihistamine, which may be responsible for some of its sedating properties.

Other common side effects of citalopram include drowsiness, insomnia, nausea, weight changes (usually weight gain), increase in appetite, vivid dreaming, frequent urination, dry mouth, increased sweating, trembling, diarrhoea, excessive yawning, severe tinnitus, and fatigue. Less common side effects include bruxism, vomiting, cardiac arrhythmia, blood pressure changes, dilated pupils, anxiety, mood swings, headache, hyperactivity and dizziness. Rare side effects include convulsions, hallucinations, severe allergic reactions and photosensitivity. If sedation occurs, the dose may be taken at bedtime rather than in the morning. Some data suggests citalopram may cause nightmares. Citalopram is associated with a higher risk of arrhythmia than other SSRIs.

Withdrawal symptoms can occur when this medicine is suddenly stopped, such as paraesthesia, sleeping problems (difficulty sleeping and intense dreams), feeling dizzy, agitated or anxious, nausea, vomiting, tremors, confusion, sweating, headache, diarrhoea, palpitations, changes in emotions, irritability, and eye or eyesight problems. Treatment with citalopram should be reduced gradually when treatment is finished.

Citalopram and other SSRIs can induce a mixed state, especially in those with undiagnosed bipolar disorder.  According to an article published in 2020, one of the other rare side effects of Citalopram could be triggering visual snow syndrome; which does not resolve after the discontinuation of the medicine.

Sexual Dysfunction

Some people experience persistent sexual side effects after they stop taking SSRIs. This is known as Post-SSRI Sexual Dysfunction (PSSD). Common symptoms in these cases include genital anaesthesia, erectile dysfunction, anhedonia, decreased libido, premature ejaculation, vaginal lubrication issues, and nipple insensitivity in women. The prevalence of PSSD is unknown, and there is no established treatment.

Abnormal Heart Rhythm

In August 2011, the US Food and Drug Administration (FDA) announced, “Citalopram causes dose-dependent QT interval prolongation. Citalopram should no longer be prescribed at doses greater than 40 mg per day”. A further clarification issued in March 2012, restricted the maximum dose to 20 mg for subgroups of patients, including those older than 60 years and those taking an inhibitor of cytochrome P450 2C19.7.

Endocrine Effects

As with other SSRIs, citalopram can cause an increase in serum prolactin level. Citalopram has no significant effect on insulin sensitivity in women of reproductive age and no changes in glycaemic control were seen in another trial.

Exposure in Pregnancy

Antidepressant exposure (including citalopram) during pregnancy is associated with shorter duration of gestation (by three days), increased risk of preterm delivery (by 55%), lower birth weight (by 75 g), and lower Apgar scores (by <0.4 points). Antidepressant exposure is not associated with an increased risk of spontaneous abortion. It is uncertain whether there is an increased prevalence of septal heart defects among children whose mothers were prescribed an SSRI in early pregnancy.

Interactions

Citalopram should not be taken with St John’s wort, tryptophan or 5-HTP as the resulting drug interaction could lead to serotonin syndrome. With St John’s wort, this may be caused by compounds in the plant extract reducing the efficacy of the hepatic cytochrome P450 enzymes that process citalopram. It has also been suggested that such compounds, including hypericin, hyperforin and flavonoids, could have SSRI-mimetic effects on the nervous system, although this is still subject to debate. One study found that Hypericum extracts had similar effects in treating moderate depression as citalopram, with fewer side effects.

Tryptophan and 5-HTP are precursors to serotonin. When taken with an SSRI, such as citalopram, this can lead to levels of serotonin that can be lethal. This may also be the case when SSRIs are taken with SRAs (serotonin releasing agents) such as in the case of MDMA. It is possible that SSRIs could reduce the effects associated due to an SRA, since SSRIs stop the reuptake of Serotonin by blocking SERT. This would allow less serotonin in and out of the transporters, thus decreasing the likelihood of neurotoxic effects. However, these concerns are still disputed as the exact pharmacodynamic effects of citalopram and MDMA have yet to be fully identified.[citation needed]

SSRIs, including citalopram, can increase the risk of bleeding, especially when coupled with aspirin, NSAIDs, warfarin, or other anticoagulants. Citalopram is contraindicated in individuals taking MAOIs, owing to a potential for serotonin syndrome.

Taking citalopram with omeprazole may cause higher blood levels of citalopram. This is a potentially dangerous interaction, so dosage adjustments may be needed or alternatives may be prescribed.

SSRI discontinuation syndrome has been reported when treatment is stopped. It includes sensory, gastrointestinal symptoms, dizziness, lethargy, and sleep disturbances, as well as psychological symptoms such as anxiety/agitation, irritability, and poor concentration. Electric shock-like sensations are typical for SSRI discontinuation. Tapering off citalopram therapy, as opposed to abrupt discontinuation, is recommended in order to diminish the occurrence and severity of discontinuation symptoms. Some doctors choose to switch a patient to Prozac (fluoxetine) when discontinuing citalopram as fluoxetine has a much longer half-life (i.e. stays in the body longer compared to citalopram). This may avoid many of the severe withdrawal symptoms associated with citalopram discontinuation. This can be done either by administering a single 20 mg dose of fluoxetine or by beginning on a low dosage of fluoxetine and slowly tapering down. Either of these prescriptions may be written in liquid form to allow a very slow and gradual tapering down in dosage. Alternatively, a patient wishing to stop taking citalopram may visit a compounding pharmacy where their prescription may be re-arranged into progressively smaller dosages.

Overdose

Overdosage may result in vomiting, sedation, disturbances in heart rhythm, dizziness, sweating, nausea, tremor, and rarely amnesia, confusion, coma, or convulsions.  Overdose deaths have occurred, sometimes involving other drugs, but also with citalopram as the sole agent. Citalopram and N-desmethylcitalopram may be quantified in blood or plasma to confirm a diagnosis of poisoning in hospitalised patients or to assist in a medicolegal death investigation. Blood or plasma citalopram concentrations are usually in a range of 50-400 μg/l in persons receiving the drug therapeutically, 1000-3000 μg/l in patients who survive acute overdosage and 3-30 mg/l in those who do not survive. It is the most dangerous of SSRIs in overdose.

Suicidality

In the United States, citalopram carries a boxed warning stating it may increase suicidal thinking and behaviour in those under age 24.

Stereochemistry

Citalopram has one stereocentre, to which a 4-fluoro phenyl group and an N, N-dimethyl-3-aminopropyl group bind. As a result of this chirality, the molecule exists in (two) enantiomeric forms (mirror images). They are termed S-(+)-citalopram and R-(–)-citalopram.

Citalopram is sold as a racemic mixture, consisting of 50% (R)-(−)-citalopram and 50% (S)-(+)-citalopram. Only the (S)-(+) enantiomer has the desired antidepressant effect. Lundbeck now markets the (S)-(+) enantiomer, the generic name of which is escitalopram. Whereas citalopram is supplied as the hydrobromide, escitalopram is sold as the oxalate salt (hydrooxalate). In both cases, the salt forms of the amine make these otherwise lipophilic compounds water-soluble.

Metabolism

Citalopram is metabolised in the liver mostly by CYP2C19, but also by CYP3A4 and CYP2D6. Metabolites desmethylcitalopram and didesmethylcitalopram are significantly less energetic and their contribution to the overall action of citalopram is negligible. The half-life of citalopram is about 35 hours. Approximately 80% is cleared by the liver and 20% by the kidneys. The elimination process is slower in the elderly and in patients with liver or kidney failure. With once-daily dosing, steady plasma concentrations are achieved in about a week. Potent inhibitors of CYP2C19 and 3A4 might decrease citalopram clearance. Tobacco smoke exposure was found to inhibit the biotransformation of citalopram in animals, suggesting that the elimination rate of citalopram is decreased after tobacco smoke exposure. After intragastric administration, the half-life of the racemic mixture of citalopram was increased by about 287%.

Society and Culture

Brand Names

Citalopram is sold under these brand names:

  • Akarin (Denmark, Nycomed).
  • C Pram S (India).
  • Celapram (Australia and New Zealand).
  • Celexa (US and Canada, Forest Laboratories, Inc.).
  • Celica (Australia).
  • Ciazil (Australia and New Zealand).
  • Cilate (South Africa).
  • Cilift (South Africa).
  • Cimal (South America, by Roemmers and Recalcine).
  • Cipralex (South Africa).
  • Cipram (Denmark and Turkey, H. Lundbeck A/S).
  • Cipramil (Australia, Brazil, Belgium, Chile, Finland, Germany, Netherlands, Iceland, Ireland, Israel, New Zealand, Norway, Russia, South Africa, Sweden, and the United Kingdom).
  • Cipraned, Cinapen (Greece).
  • Ciprapine (Ireland).
  • Ciprotan (Ireland).
  • Citabax, Citaxin (Poland).
  • Cital (Poland).
  • Citalec (Czech Republic and Slovakia).
  • Citalex (Iran and Serbia).
  • Citalo (Australia, Egypt, and Pakistan).
  • Citalopram (Canada, Denmark, Finland, Germany, Ireland, New Zealand, Spain, Sweden, Switzerland, United Kingdom, the US).
  • Citol (Russia).
  • Citox (Mexico).
  • Citrol (Europe and Australia).
  • Citta (Brazil).
  • Dalsan (Eastern Europe).
  • Denyl (Brazil).
  • Elopram (Italy).
  • Estar (Pakistan).
  • Humorup (Argentina).
  • Humorap (Peru, Bolivia).
  • Lopraxer (Greece).
  • Oropram (Iceland, Actavis).
  • Opra (Russia).
  • Pram (Russia).
  • Pramcit (Pakistan).
  • Procimax (Brazil).
  • Recital (Israel, Thrima Inc. for Unipharm Ltd.).
  • Sepram (Finland).
  • Seropram (various European countries, including Czech Republic).
  • Szetalo (India).
  • Talam (Europe and Australia).
  • Temperax (Argentina, Chile, and Peru).
  • Vodelax (Turkey).
  • Zentius (South America, by Roemmers and Recalcine).
  • Zetalo (India).
  • Cipratal (Kuwait, GCC).
  • Zylotex (Portugal).

European Commission Fine

On 19 June 2013, the European Commission imposed a fine of €93.8 million on the Danish pharmaceutical company Lundbeck, plus a total of €52.2 million on several generic pharmaceutical-producing companies. This was in response to Lundbeck entering an agreement with the companies to delay their sales of generic citalopram after Lundbeck’s patent on the drug had expired, thus reducing competition in breach of European antitrust law.

What is a Second-Generation Antidepressant?

Published on by Andrew Marshall1 Comment

Introduction

The second-generation antidepressants are a class of antidepressants characterised primarily by the era of their introduction, approximately coinciding with the 1970s and 1980s, rather than by their chemical structure or by their pharmacological effect. As a consequence, there is some controversy over which treatments actually belong in this class.

Refer to Atypical Antidepressant, Tricyclic Antidepressant, and Tetracyclic Antidepressant.

The term “third generation antidepressant” is sometimes used to refer to newer antidepressants, from the 1990s and 2000s, often selective serotonin reuptake inhibitors (SSRIs) such as; fluoxetine (Prozac), paroxetine (Paxil) and sertraline (Zoloft), as well as some non-SSRI antidepressants such as mirtazapine, nefazodone, venlafaxine, duloxetine and reboxetine. However, this usage is not universal.

Examples

This list is not exhaustive, and different sources vary upon which items should be considered second-generation.

  • Amineptine.
  • Amoxapine.
  • Bupropion.
  • Iprindole.
  • Maprotiline.
  • Medifoxamine.
  • Mianserin.
  • Nomifensine.
  • Tianeptine.
  • Trazodone.
  • Venlafaxine.
  • Viloxazine.

What is Seproxetine?

Published on by Andrew MarshallLeave a comment

Introduction

Seproxetine, also known as (S)-norfluoxetine, is a selective serotonin reuptake inhibitor (SSRI).

Background

It is the S enantiomer of norfluoxetine, the main active metabolite of the widely used antidepressant fluoxetine; but little is known about its pharmacological actions. Seproxetine was being investigated by Eli Lilly and Company as an antidepressant; however, cardiac side effects were discovered and development was discontinued.

What is RTI-353?

Published on by Andrew MarshallLeave a comment

Introduction

RTI(-4229)-353 is a phenyltropane derived drug which acts as an SSRI (Navarro et al., 2001).

Tamagnan et al. (2006) also made some phenyltropanes with high activity and selectivity for the SERT (pM affinity).

References

Navarro, H.A., Xu, H., Zhong, D., Blough, B.E., Ross, W.P., Kuhar, M.J. & Carroll, F.I. (2001) [(125)I]3beta-(4-ethyl-3-iodophenyl)nortropane-2beta-carboxylic acid methyl ester ([(125)I]EINT): a potent and selective radioligand for the brain serotonin transporter. Synapse: New York, N.Y. 41(3), pp.241-247.

Tamagnan, G., Alagille, D., Fu, X., Kula, N.S., Baldessarini, R.J., Innis, R.B. & Baldwin, R.M. (2006) Synthesis and monoamine transporter affinity of new 2beta-carbomethoxy-3beta-[aryl or heteroaryl]phenyltropanes. Bioorganic & Medicinal Chemistry Letters. 16(1), pp.217-220.