Methylenedioxypyrovalerone (abbreviated MDPV, and also called monkey dust) is a stimulant of the cathinone class that acts as a norepinephrine–dopamine reuptake inhibitor (NDRI). It was first developed in the 1960s by a team at Boehringer Ingelheim. Its activity at the dopamine transporter is six times stronger than at the norepinephrine transporter and it is virtually inactive at the serotonin transporter. MDPV remained an obscure stimulant until around 2004 when it was reportedly sold as a designer drug. In the US, products containing MDPV and labelled as bath salts were sold as recreational drugs in gas stations, similar to the marketing for Spice and K2 as incense, until it was banned in 2011.
Appearance
The hydrochloride salt exists as a very fine crystalline powder; it is hygroscopic and thus tends to form clumps, resembling something like powdered sugar. Its colour can range from pure white to a yellowish-tan and has a slight odour that strengthens as it colours. Impurities are likely to consist of either pyrrolidine or alpha-dibrominated alkylphenones—respectively, from either excess pyrrolidine or incomplete amination during synthesis. These impurities likely account for its discoloration and fishy (pyrrolidine) or bromine-like odour, which worsens upon exposure to air, moisture, or bases.
Pharmacology
Methylenedioxypyrovalerone has no record of FDA approved medical use. It has been shown to produce robust reinforcing effects and compulsive self-administration in rats, though this had already been provisionally established by a number of documented cases of misuse and addiction in humans before the animal tests were carried out.
MDPV is the 3,4-methylenedioxy ring-substituted analogue of the compound pyrovalerone, developed in the 1960s, which has been used for the treatment of chronic fatigue and as an anorectic, but caused problems of abuse and dependence.
Other drugs with a similar chemical structure include α-pyrrolidinopropiophenone (α-PPP), 4′-methyl-α-pyrrolidinopropiophenone (M-α-PPP), 3′,4′-methylenedioxy-α-pyrrolidinopropiophenone (MDPPP) and 1-phenyl-2-(1-pyrrolidinyl)-1-pentanone (α-PVP).
Effects
MDPV acts as a stimulant and has been reported to produce effects similar to those of cocaine, methylphenidate, and amphetamines.
The primary psychological effects have a duration of roughly 3 to 4 hours, with aftereffects such as tachycardia, hypertension, and mild stimulation lasting from 6 to 8 hours. High doses have been observed to cause intense, prolonged panic attacks in stimulant-intolerant users, and there are anecdotal reports of psychosis from sleep withdrawal and addiction at higher doses or more frequent dosing intervals. It has also been repeatedly noted to induce irresistible cravings to re-administer.
Reported modalities of intake include oral consumption, insufflation, smoking, rectal and intravenous use. It is supposedly active at 3–5 mg, with typical doses ranging between 5–20 mg.
When assayed in mice, repeated exposure to MDPV causes not only an anxiogenic effect (the opposite of anxiolytic) but also increased aggressive behaviour, a feature that has already been observed in humans. As with MDMA, MDPV also caused a faster adaptation to repeated social isolation.
A cross-sensitisation between MDPV and cocaine has been evidenced. Furthermore, both psychostimulants, MDPV and cocaine, restore drug-seeking behaviour with respect to each other, although relapse into drug-taking is always more pronounced with the conditioning drug. Moreover, memories associated with MDPV require more time to be extinguished. Also, in MDPV-treated mice, a priming-dose of cocaine triggers significant neuroplasticity, implying a high vulnerability to its abuse.
Long-Term Effects
The long-term effects of MDPV on humans have not been studied, but it has been reported that mice treated with MDPV during adolescence show reinforcing behaviour patterns to cocaine that are higher than the control groups. These behavioural changes are related to alterations of factor expression directly related to addiction. All this suggests an increased vulnerability to cocaine abuse.
Metabolism
MDPV undergoes CYP450 2D6, 2C19, 1A2, and COMT phase 1 metabolism (liver) into methylcatechol and pyrrolidine, which in turn are glucuronated (uridine 5′-diphospho-glucuronosyl-transferase) allowing it to be excreted by the kidneys, with only a small fraction of the metabolites being excreted into the stools.[20] No free pyrrolidine will be detected in the urine.
Molecularly, this is seen as demethylenation of methylenedioxypyrovalerone (CYP2D6), followed by methylation of the aromatic ring via catechol-O-methyl transferase. Hydroxylation of both the aromatic ring and side chain then takes place, followed by an oxidation of the pyrrolidine ring to the corresponding lactam, with subsequent detachment and ring opening to the corresponding carboxylic acid.
Detection in Biological Specimens
MDPV may be quantified in blood, plasma or urine by gas chromatography-mass spectrometry or liquid chromatography-mass spectrometry to confirm a diagnosis of poisoning in hospitalised patients or to provide evidence in a medicolegal death investigation. Blood or plasma MDPV concentrations are expected to be in a range of 10–50 μg/L in persons using the drug recreationally, >50 μg/L in intoxicated patients, and >300 μg/L in victims of acute overdose.
Legality
In 2010, a 33-year-old Swedish man was sentenced to six years in prison by an appellate court, Hovrätt, for possession of 250 grams of MDPV that had been acquired prior to criminalisation.
Australia
In Western Australia, MDPV has been banned under the Poisons Act 1964, having been included in Appendix A Schedule 9 of the Poisons Act 1964 as from February 11, 2012. The Director of Public Prosecutions for Western Australia announced that anyone intending to sell or supply MDPV faces a maximum $100,000 fine or 25 years in jail. Users face a $2000 fine or two years’ jail. Therefore, anyone caught with MDPV can be charged with possession, selling, supplying or intent to sell or supply.
Canada
Canadian Health Minister Leona Aglukkaq announced on 05 June 2012, that MDPV would be listed on Schedule I of the Controlled Drugs and Substances Act, which was realised on 26 September 2012.
Finland
MDPV is specifically listed as a controlled substance in Finland (listed appendix IV substance as of 28 June 2010).
United Kingdom
In the UK, following the ACMD’s report on substituted cathinone derivatives, MDPV is a Class B drug under The Misuse of Drugs Act 1971 (Amendment) Order 2010, making it illegal to sell, buy, or possess without a license.
United States
In the United States, MDPV is a Drug Enforcement Agency (DEA) federally scheduled drug. On 21 October 2011, the DEA issued a temporary one-year ban on MDPV, classifying it as a schedule I substance. Schedule I status is reserved for substances with a high potential for abuse, no currently accepted use for treatment in the United States and a lack of accepted safety standards for use under medical supervision.
Before the federal ban was announced, MDPV was already banned in Louisiana and Florida. On 24 March 2011, Kentucky passed bill HB 121, which makes MDPV, as well as three other cathinones, controlled substances in the state. It also makes it a Class A misdemeanour to sell the drug, and a Class B misdemeanour to possess it.
MDPV is banned in New Jersey under Pamela’s Law. The law is named after Pamela Schmidt, a Rutgers University student who was murdered in March 2011 by an alleged user of MDPV. A toxicology report later found no “bath salts” in his system.
On 05 May 2011, Tennessee Governor Bill Haslam signed a law making it a crime “to knowingly produce, manufacture, distribute, sell, offer for sale or possess with intent to produce, manufacture, distribute, sell, or offer for sale” any product containing MDPV.
On 06 July 2011, the governor of Maine signed a bill establishing fines for possession and penalties for trafficking of MDPV.
On 17 October 2011, an Ohio law banning synthetic drugs took effect barring selling and/or possession of “any material, compound, mixture, or preparation that contains any quantity of the following substances having a stimulant effect on the central nervous system, including their salts, isomers, and salts of isomers”, listing ephedrine and pyrovalerone. It also specifically includes MDPV. Four days after this Ohio law was passed, the DEA’s national emergency ban was implemented.
On 08 December 2011, under the Synthetic Drug Control Act, the US House of Representatives voted to ban MDPV and a variety of other synthetic drugs that had been legally sold in stores.
Documented Fatalities
In April 2011, two weeks after being reported missing, two men in northwestern Pennsylvania were found dead in a remote location on government land. The official cause of death of both men was hypothermia, but toxicology reports later confirmed that both Troy Johnson, 29, and Terry Sumrow, 28, had ingested MDPV shortly before their deaths. “It wasn’t anything to kill them, but enough to get them messed up,” the county coroner said. MDPV containers were found in their vehicle along with spoons, hypodermic syringes and marijuana paraphernalia. In April 2011, an Alton, Illinois, woman apparently died from an MDPV overdose. In May 2011, the CDC reported a hospital emergency department (ED) visit after the use of “bath salts” in Michigan. One person was reported dead on arrival at the ED. Associates of the dead person reported that he had used bath salts. His toxicology results revealed high levels of MDPV in addition to marijuana and prescription drugs. The primary factor contributing to death was cited as MDPV toxicity after autopsy was performed. An incident of hemiplegia has been reported.
A total of 107 non-fatal intoxications and 99 analytically confirmed deaths related to MDPV between September 2009 and August 2013 were reported by nine European countries.
Overdose Treatment
Physicians often treat MDPV overdose cases with anxiolytics, such as benzodiazepines, to lessen the drug-induced activity in the brain and body. In some cases, general anaesthesia was used because sedatives were ineffective.
Treatment in the emergency department for hypertensive emergency, tachycardia, agitation, or seizures consists of large doses of lorazepam in 2–4 mg increments every 10–15 minutes intravenously or intramuscularly. If this is not effective, haloperidol is an alternative treatment. It is suggested that the use of beta blockers to treat hypertension in these patients can cause an unopposed peripheral alpha-adrenergic effect with a dangerous paradoxical rise in blood pressure. Electroconvulsive therapy (ECT) has been shown to improve persistent psychotic symptoms associated with repeated MDPV use.
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A serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI), also known as a triple reuptake inhibitor (TRI), is a type of drug that acts as a combined reuptake inhibitor of the monoamine neurotransmittersserotonin, norepinephrine, and dopamine. It does this by concomitantly inhibiting the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT), respectively. Inhibition of the reuptake of these neurotransmitters increases their extracellular concentrations and, therefore, results in an increase in serotonergic, adrenergic, and dopaminergic neurotransmission. The naturally-occurring and potent SNDRI cocaine is widely used recreationally and often illegally for the euphoric effects it produces.
Other SNDRIs were developed as potential antidepressants and treatments for other disorders, such as obesity, cocaine addiction, attention-deficit hyperactivity disorder (ADHD), and chronic pain. They are an extension of selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) whereby the addition of dopaminergic action is thought to have the possibility of heightening therapeutic benefit. However, increased side effects and abuse potential are potential concerns of these agents relative to their SSRI and SNRI counterparts.
The SNDRIs are similar to non-selective monoamine oxidase inhibitors (MAOIs) such as phenelzine and tranylcypromine in that they increase the action of all three of the major monoamine neurotransmitters. They are also similar to serotonin–norepinephrine–dopamine releasing agents (SNDRAs) like MDMA (“ecstasy”) and α-ethyltryptamine (αET) for the same reason, although they act via a different mechanism and have differing physiological and qualitative effects.
Although their primary mechanisms of action are as NMDA receptor antagonists, ketamine and phencyclidine are also SNDRIs and are similarly encountered as drugs of abuse.
Indications
Depression
Major depressive disorder (MDD) is the foremost reason supporting the need for development of an SNDRI. According to the World Health Organisation (WHO), depression is the leading cause of disability and the 4th leading contributor to the global burden of disease in 2000. By the year 2020, depression is projected to reach 2nd place in the ranking of DALYs (disability adjusted life years).
About 16% of the population is estimated to be affected by major depression, and another 1% is affected by bipolar disorder, one or more times throughout an individual’s lifetime. The presence of the common symptoms of these disorders are collectively called ‘depressive syndrome’ and includes a long-lasting depressed mood, feelings of guilt, anxiety, and recurrent thoughts of death and suicide. Other symptoms including poor concentration, a disturbance of sleep rhythms (insomnia or hypersomnia), and severe fatigue may also occur. Individual patients present differing subsets of symptoms, which may change over the course of the disease highlighting its multifaceted and heterogeneous nature. Depression is often highly comorbid with other diseases, e.g. cardiovascular disease (myocardial infarction, stroke), diabetes, cancer, Depressed subjects are prone to smoking, substance abuse, eating disorders, obesity, high blood pressure, pathological gambling and internet addiction, and on average have a 15 to 30 year shorter lifetime compared with the general population.
Major depression can strike at virtually any time of life as a function of genetic and developmental pre-disposition in interaction with adverse life-events. Although common in the elderly, over the course of the last century, the average age for a first episode has fallen to ~30 years. However, depressive states (with subtly different characteristics) are now frequently identified in adolescents and even children. The differential diagnosis (and management) of depression in young populations requires considerable care and experience; for example, apparent depression in teenagers may later transpire to represent a prodromal phase of schizophrenia.
The ability to work, familial relationships, social integration, and self-care are all severely disrupted.
The genetic contribution has been estimated as 40-50%. However, combinations of multiple genetic factors may be involved because a defect in a single gene usually fails to induce the multifaceted symptoms of depression.
Pharmacotherapy
There remains a need for more efficacious antidepressant agents. Although two-thirds of patients will ultimately respond to antidepressant treatment, one-third of patients respond to placebo, and remission is frequently sub-maximal (residual symptoms). In addition to post-treatment relapse, depressive symptoms can even recur in the course of long-term therapy (tachyphylaxis). Also, currently available antidepressants all elicit undesirable side-effects, and new agents should be divested of the distressing side-effects of both first and second-generation antidepressants.
Another serious drawback of all antidepressants is the requirement for long-term administration prior to maximal therapeutic efficacy. Although some patients show a partial response within 1–2 weeks, in general one must reckon with a delay of 3–6 weeks before full efficacy is attained. In general, this delay to onset of action is attributed to a spectrum of long-term adaptive changes. These include receptor desensitisation, alterations in intracellular transduction cascades and gene expression, the induction of neurogenesis, and modifications in synaptic architecture and signalling.
Depression has been associated with impaired neurotransmission of serotonergic (5-HT), noradrenergic (NE), and dopaminergic (DA) pathways, although most pharmacologic treatment strategies directly enhance only 5-HT and NE neurotransmission. In some patients with depression, DA-related disturbances improve upon treatment with antidepressants, it is presumed by acting on serotonergic or noradrenergic circuits, which then affect DA function. However, most antidepressant treatments do not directly enhance DA neurotransmission, which may contribute to residual symptoms, including impaired motivation, concentration, and pleasure.
Preclinical and clinical research indicates that drugs inhibiting the reuptake of all three of these neurotransmitters can produce a more rapid onset of action and greater efficacy than traditional antidepressants.
DA may promote neurotrophic processes in the adult hippocampus, as 5-HT and NA do. It is thus possible that the stimulation of multiple signalling pathways resulting from the elevation of all three monoamines may account, in part, for an accelerated and/or greater antidepressant response.
Dense connections exist between monoaminergic neurons. Dopaminergic neurotransmission regulates the activity of 5-HT and NE in the dorsal raphe nucleus (DR) and locus coeruleus (LC), respectively. In turn, the ventral tegmental area (VTA) is sensitive to 5-HT and NE release.
In the case of SSRIs, the promiscuity among transporters means that there may be more than a single type of neurotransmitter to consider (e.g. 5-HT, DA, NE, etc.) as mediating the therapeutic actions of a given medication. MATs are able to transport monoamines other than their “native” neurotransmitter. It was advised to consider the role of the organic cation transporters (OCT) and the plasma membrane monoamine transporter (PMAT).
To examine the role of monoamine transporters in models of depression DAT, NET, and SERT knockout (KO) mice and wild-type littermates were studied in the forced swim test (FST), the tail suspension test, and for sucrose consumption. The effects of DAT KO in animal models of depression are larger than those produced by NET or SERT KO, and unlikely to be simply the result of the confounding effects of locomotor hyperactivity; thus, these data support re-evaluation of the role that DAT expression could play in depression and the potential antidepressant effects of DAT blockade.
The SSRIs were intended to be highly selective at binding to their molecular targets. However it may be an oversimplification, or at least controversial in thinking that complex psychiatric (and neurological) diseases are easily solved by such a monotherapy. While it may be inferred that dysfunction of 5-HT circuits is likely to be a part of the problem, it is only one of many such neurotransmitters whose signalling can be affected by suitably designed medicines attempting to alter the course of the disease state.
Most common CNS disorders are highly polygenic in nature; that is, they are controlled by complex interactions between numerous gene products. As such, these conditions do not exhibit the single gene defect basis that is so attractive for the development of highly-specific drugs largely free of major undesirable side-effects (“the magic bullet”). Second, the exact nature of the interactions that occur between the numerous gene products typically involved in CNS disorders remain elusive, and the biological mechanisms underlying mental illnesses are poorly understood.
Clozapine is an example of a drug used in the treatment of certain CNS disorders, such as schizophrenia, that has superior efficacy precisely because of its broad-spectrum mode of action. Likewise, in cancer chemotherapeutics, it has been recognised that drugs active at more than one target have a higher probability of being efficacious.
In addition, the nonselective MAOIs and the TCA SNRIs are widely believed to have an efficacy that is superior to the SSRIs normally picked as the first-line choice of agents for/in the treatment of MDD and related disorders. The reason for this is based on the fact that SSRIs are safer than nonselective MAOIs and TCAs. This is both in terms of there being less mortality in the event of overdose, but also less risk in terms of dietary restrictions (in the case of the nonselective MAOIs), hepatotoxicity (MAOIs) or cardiotoxicity (TCAs).
Mazindol (Mazanor, Sanorex) — anorectic; ki is 50 nM for SERT, 18 nM for NET, 45 nM for DAT[38]
Nefazodone (Serzone, Nefadar, Dutonin) — antidepressant; non-selective; ki is 200 nM at SERT, 360 nM at NET, 360 nM at DAT
Nefopam (ki SER/NE/DA = 29/33/531 nM) Informative review.
Sibutramine (Meridia) is a withdrawn anorectic that is an SNDRI in vitro with ki values of 298 nM at SERT, 5451 at NET, 943 nM at DAT. However, it appears to act as a prodrug in vivo to metabolites that are considerably more potent and possess different ratios of monoamine reuptake inhibition in comparison, and in accordance, sibutramine behaves contrarily as an SNRI (73% and 54% for norepinephrine and serotonin reuptake inhibition, respectively) in human volunteers with only very weak and probably inconsequential inhibition of dopamine reuptake (16%).
Venlafaxine (Effexor) is sometimes referred to as an SNDRI, but is extremely imbalanced with ki values of 82 nM for SERT, 2480 nM for NET, and 7647 nM for DAT, with a ratio of 1:30:93. It may weakly inhibit the reuptake of dopamine at high doses.
Coincidental
Esketamine (Ketanest S) — anesthetic; S-enantiomer of ketamine; weak SNDRI action likely contributes to effects and abuse potential
Ketamine (Ketalar) — anesthetic and dissociative drug of abuse; weak SNDRI action likely contributes to effects and abuse potential
Phencyclidine (Sernyl) — discontinued anaesthetic and dissociative psychostimulant drug of abuse; SNDRI action likely contributes to effects and abuse potential
Tripelennamine (Pyribenzamine) — antihistamine; weak SNDRI; sometimes abused for this reason
Centanafadine (EB-1020) — see here for details Archived 2012-05-31 at the Wayback Machine 1 to 6 to 14 ratio for NDS. Completed Phase 3 trials for ADHD.
Toxicological screening is important to ensure safety of the drug molecules. In this regard, the p m-dichloro phenyl analogue of venlafaxine was dropped from further development after its potential mutagenicity was called into question. The mutagenicity of this compound is still doubtful though. It was dropped for other reasons likely related to speed at which it could be released onto the market relative to the more developed compound venlafaxine. More recently, the carcinogenicity of PRC200-SS was likewise reported.
(+)-CPCA (“nocaine”) is the 3R,4S piperidine stereoisomer of (phenyltropane based) RTI-31. It is non addictive, although this might be due to it being a NDRI, not a SNDRI. The β-naphthyl analogue of “Nocaine” is a SNDRI though in the case of both the SS and RR enantiomers. Consider the piperidine analogues of brasofensine and tesofensine. These were prepared by NeuroSearch (In Denmark) by the chemists Peter Moldt (2002), and Frank Wätjen (2004–2009). There are four separate isomers to consider (SS, RR, S/R and R/S). This is because there are two chiral carbon sites of asymmetry (means 2 to the power of n isomers to consider where n is the number of chiral carbons). They are therefore a diastereo(iso)meric pair of racemers. With a racemic pair of diastereomers, there is still the question of syn (cis) or anti (trans). In the case of the phenyltropanes, although there are four chiral carbons, there are only eight possible isomers to consider. This is based on the fact that the compound is bicyclic and therefore does not adhere to the equation given above.
It is complicated to explain which isomers are desired. For example, although Alan P. Kozikowski showed that R/S nocaine is less addictive than SS Nocaine, studies on variously substituted phenyltropanes by F. Ivy Carroll et at. revealed that the ββ isomers were less likely to cause convulsions, tremor and death than the corresponding trans isomers (more specifically, what is meant is the 1R,2R,3S isomers). While it does still have to be conceded that RTI-55 caused death at a dosage of 100 mg/kg, its therapeutic index of safety is still much better than the corresponding trans isomers because it is a more potent compound.
In discussing cocaine and related compounds such as amphetamines, it is clear that these psychostimulants cause increased blood pressure, decreased appetite (and hence weight loss), increased locomotor activity (LMA) etc. In the United States, cocaine overdose is one of the leading causes of ER admissions each year due to drug overdose. People are at increased risk of heart attack and stroke and also present with an array of psychiatric symptoms including anxiety & paranoia etc. On removal of the 2C tropane bridge and on going from RTI-31 to the simpler SS and RS Nocaine it was seen that these compounds still possessed activity as NDRIs but were not powerful psychostimulants. Hence, this might be viewed as a strategy for increasing the safety of the compounds and would also be preferable to use in patients who are not looking to achieve weight loss.
In light of the above paragraph, another way of reducing the psychomotor stimulant and addictive qualities of phenyltropane stimulants is in picking one that is relatively serotonergic. This strategy was employed with success for RTI-112.
Another thing that is important and should be mentioned is the risk for serotonin syndrome when incorporating the element of 5-HT transporter inhibition into a compound that is already fully active as a NDRI (or vice versa). The reasons for serotonin syndrome are complicated and not fully understood.
Addiction
Drug addiction may be regarded as a disease of the brain reward system. This system, closely related to the system of emotional arousal, is located predominantly in the limbic structures of the brain. Its existence was proved by demonstration of the “pleasure centres,” that were discovered as the location from which electrical self-stimulation is readily evoked. The main neurotransmitter involved in the reward is dopamine, but other monoamines and acetylcholine may also participate. The anatomical core of the reward system are dopaminergic neurons of the ventral tegmentum that project to the nucleus accumbens, amygdala, prefrontal cortex and other forebrain structures.
There are several groups of substances that activate the reward system and they may produce addiction, which in humans is a chronic, recurrent disease, characterised by absolute dominance of drug-seeking behaviour.
According to various studies, the relative likelihood of rodents and non-human primates self-administering various psychostimulants that modulate monoaminergic neurotransmission is lessened as the dopaminergic compounds become more serotonergic.
The above finding has been found for amphetamine and some of its variously substituted analogues including PAL-287 etc.
RTI-112 is another good example of the compound becoming less likely to be self-administered by the test subject in the case of a dopaminergic compound that also has a marked affinity for the serotonin transporter.
WIN 35428, RTI-31, RTI-51 and RTI-55 were all compared and it was found that there was a negative correlation between the size of the halogen atom and the rate of self-administration (on moving across the series). Rate of onset was held partly accountable for this, although increasing the potency of the compounds for the serotonin transporter also played a role.
Further evidence that 5-HT dampens the reinforcing actions of dopaminergic medications comes from the co-administration of psychostimulants with SSRIs, and the phen/fen combination was also shown to have limited abuse potential relative to administration of phentermine only.
NET blockade is unlikely to play a major role in mediating addictive behaviour. This finding is based on the premise that desipramine is not self-administered, and also the fact that the NRI atomoxetine was not reinforcing. However, it was still shown to facilitate dopaminergic neurotransmission in certain brain regions such as in the core of the prefrontal cortex (PFC).
Relation to Cocaine
Cocaine is a short-acting SNDRI that also exerts auxiliary pharmacological actions on other receptors. Cocaine is a relatively “balanced” inhibitor, although facilitation of dopaminergic neurotransmission is what has been linked to the reinforcing and addictive effects. In addition, cocaine has some serious limitations in terms of its cardiotoxicity due to its local anaesthetic activity. Thousands of cocaine users are admitted to emergency units in the USA every year because of this; thus, development of safer substitute medications for cocaine abuse could potentially have significant benefits for public health.
Many of the SNDRIs currently being developed have varying degrees of similarity to cocaine in terms of their chemical structure. There has been speculation over whether the new SNDRIs will have an abuse potential like cocaine does. However, for pharmacotherapeutical treatment of cocaine addiction it is advantageous if a substitute medication is at least weakly reinforcing because this can serve to retain addicts in treatment programmes:
… limited reinforcing properties in the context of treatment programs may be advantageous, contributing to improved patient compliance and enhanced medication effectiveness.
However, not all SNDRIs are reliably self-administered by animals. Examples include:
PRC200-SS was not reliably self-administered.
RTI-112 was not self-administered because at low doses the compound preferentially occupies the SERT and not the DAT.
Tesofensine was also not reliably self-administered by human stimulant addicts.
The nocaine analogue JZAD-IV-22 only partly substituted for cocaine in animals, but produced none of the psychomotor activation of cocaine, which is a trait marker for stimulant addiction.
Legality
Cocaine is a controlled drug (Class A in the UK; Schedule II in the USA); it has not been entirely outlawed in most countries, as despite having some “abuse potential” it is recognised that it does have medical uses.
Brasofensine was made “class A” in the UK under the MDA (misuse of drugs act). The semi-synthetic procedure for making BF uses cocaine as the starting material.
Naphyrone first appeared in 2006 as one of quite a large number of analogues of pyrovalerone designed by the well-known medicinal chemist P. Meltzer et al. When the designer drugs mephedrone and methylone became banned in the United Kingdom, vendors of these chemicals needed to find a suitable replacement. Mephedrone and methylone affect the same chemicals in the brain as a SNDRI, although they are thought to act as monoamine releasers and not act through the reuptake inhibitor mechanism of activity. A short time later, mephedrone and methylone were banned (which had become quite popular by the time they were illegalised), naphyrone appeared under the trade name NRG-1. NRG-1 was promptly illegalised, although it is not known if its use resulted in any hospitalisations or deaths.
Role of Monoamine Neurotransmitters
Monoamine Hypothesis
The original monoamine hypothesis postulates that depression is caused by a deficiency or imbalances in the monoamine neurotransmitters (5-HT, NE, and DA). This has been the central topic of depression research for approximately the last 50 years; it has since evolved into the notion that depression arises through alterations in target neurons (specifically, the dendrites) in monoamine pathways.
When reserpine (an alkaloid with uses in the treatment of hypertension and psychosis) was first introduced to the West from India in 1953, the drug was unexpectedly shown to produce depression-like symptoms. Further testing was able to reveal that reserpine causes a depletion of monoamine concentrations in the brain. Reserpine’s effect on monoamine concentrations results from blockade of the vesicular monoamine transporter, leading to their increased catabolism by monoamine oxidase. However, not everyone has been convinced by claims that reserpine is depressogenic, some authors (David Healy in particular) have even claimed that it is antidepressant.
Tetrabenazine, a similar agent to reserpine, which also depletes catecholamine stores, and to a lesser degree 5-HT, was shown to induce depression in many patients.
Iproniazid, an inhibitor of MAO, was noted to elevate mood in depressed patients in the early 1950s, and soon thereafter was shown to lead to an increase in NA and 5-HT.
Hertting et al. demonstrated that the first TCA, imipramine, inhibited cellular uptake of NA in peripheral tissues. Moreover, both antidepressant agents were demonstrated to prevent reserpine-induced sedation. Likewise, administration of DOPA to laboratory animals was shown to reverse reserpine induced sedation; a finding reproduced in humans. Amphetamine, which releases NA from vesicles and prevents re-uptake was also used in the treatment of depression at the time with varying success.
In 1965 Schildkraut formulated the catecholamine theory of depression. This was subsequently the most widely cited article in the American Journal of Psychiatry. The theory stated that “some, if not all, depressions are associated with an absolute or relative deficiency of catecholamines, in particular noradrenaline (NA), at functionally important adrenergic receptor sites in the brain. However, elation may be associated with an excess of such amines.”
Shortly after Schildkraut’s catecholamine hypothesis was published, Coppen proposed that 5-HT, rather than NA, was the more important neurotransmitter in depression. This was based on similar evidence to that which produced the NA theory as reserpine, imipramine, and iproniazid affect the 5-HT system, in addition to the noradrenergic system. It was also supported by work demonstrating that if catecholamine levels were depleted by up to 20% but 5-HT neurotransmission remained unaltered there was no sedation in animals. Alongside this, the main observation promoting the 5-HT theory was that administration of a MAOI in conjunction with tryptophan (precursor of 5-HT) elevated mood in control patients and potentiated the antidepressant effect of MAOI. Set against this, combination of an MAOI with DOPA did not produce a therapeutic benefit.
Inserting a chlorine atom into imipramine leads to clomipramine, a drug that is much more SERT selective than the parent compound.
Clomipramine was a predecessor to the development of the more recent SSRIs. There was, in fact, a time prior to the SSRIs when selective NRIs were being considered (c.f. talopram and melitracen). In fact, it is also believed that the selective NRI nisoxetine was discovered prior to the invention of fluoxetine. However, the selective NRIs did not get promoted in the same way as did the SSRIs, possibly due to an increased risk of suicide. This was accounted for on the basis of the energising effect that these agents have. Moreover, NRIs have the additional adverse safety risk of hypertension that is not seen for SSRIs. Nevertheless, NRIs have still found uses.
Further support for the monoamine hypothesis came from monoamine depletion studies:
Alpha-methyl-p-tyrosine (AMPT) is a tyrosine hydroxylase enzyme inhibitor that serves to inhibit catecholamine synthesis. AMPT led to a resurgence of depressive symptoms in patients improved by the NE reuptake inhibitor (NRI) desipramine, but not by the SSRI fluoxetine. The mood changes induced by AMPT may be mediated by decreases in norepinephrine, while changes in selective attention and motivation may be mediated by dopamine.
Dietary depletion of the DA precursors phenylalanine and tyrosine does not result in the relapse of formerly depressed patients off their medication.
Administration of fenclonine (para-chlorophenylalanine) is able to bring about a depletion of 5-HT. The mechanism of action for this is via tryptophan hydroxylase inhibition. In the 1970s administration of parachlorophenylalanine produced a relapse in depressive symptoms of treated patients, but it is considered too toxic for use today.
Although depletion of tryptophan — the rate-limiting factor of serotonin synthesis — does not influence the mood of healthy volunteers and untreated patients with depression, it does produce a rapid relapse of depressive symptoms in about 50% of remitted patients who are being, or have recently been treated with serotonin selective antidepressants.
Dopaminergic
There appears to be a pattern of symptoms that are currently inadequately addressed by serotonergic antidepressants — loss of pleasure (anhedonia), reduced motivation, loss of interest, fatigue and loss of energy, motor retardation, apathy and hypersomnia. Addition of a pro-dopaminergic component into a serotonin based therapy would be expected to address some of these short-comings.
Several lines of evidence suggest that an attenuated function of the dopaminergic system may play an important role in depression:
Mood disorders are highly prevalent in pathologies characterized by a deficit in central DA transmission such as Parkinson’s disease (PD). The prevalence of depression can reach up to 50% of individuals with PD.
Patients taking strong dopaminergic antagonists such as those used in the treatment of psychosis are more likely than the general population to develop symptoms of depression.
Data from clinical studies have shown that DA agonists, such as bromocriptine, pramipexole and ropinirole, exhibit antidepressant properties.
Amineptine, a TCA-derivative that predominantly inhibits DA re-uptake and has minimal noradrenergic and serotonergic activity has also been shown to possess antidepressant activity. A number of studies have suggested that amineptine has similar efficacy to the TCAs, MAOIs and SSRIs. However, amineptine is no longer available as a treatment for depression due to reports of an abuse potential.
The B-subtype selective MAOI selegiline (a drug developed for the treatment of PD) has now been approved for the treatment of depression in the form of a transdermal patch (Emsam). For some reason, there have been numerous reports of users taking this drug in conjunction with β-phenethylamine.
Taking psychostimulants for the alleviation of depression is well proven strategy, although in a clinical setting the use of such drugs is usually prohibited because of their strong addiction propensity.
When users withdraw from psychostimulant drugs of abuse (in particular, amphetamine), they experience symptoms of depression. This is likely because the brain enters into a hypodopaminergic state, although there might be a role for noradrenaline also.
For these drugs to be reinforcing, they must block more than 50% of the DAT within a relatively short time period (<15 minutes from administration) and clear the brain rapidly to enable fast repeated administration.
In addition to mood, they may also improve cognitive performance, although this remains to be demonstrated in humans.
The rate of clearance from the body is faster for ritalin than it is for regular amphetamine.
Noradrenergic
The decreased levels of NA proposed by Schildkraut, suggested that there would be a compensatory upregulation of β-adrenoceptors. Despite inconsistent findings supporting this, more consistent evidence demonstrates that chronic treatment with antidepressants and electroconvulsive therapy (ECT) decrease β-adrenoceptor density in the rat forebrain. This led to the theory that β-adrenoceptor downregulation was required for clinical antidepressant efficacy. However, some of the newly developed antidepressants do not alter, or even increase β-adrenoceptor density.
Another adrenoceptor implicated in depression is the presynaptic α2-adrenoceptor. Chronic desipramine treatment in rats decreased the sensitivity of α2-adrenoceptors, a finding supported by the fact that clonidine administration caused a significant increase in growth hormone (an indirect measure of α2-adrenoceptor activity) although platelet studies proved inconsistent. This supersensitivity of α2-adrenoceptor was postulated to decrease locus coeruleus (the main projection site of NA in the central nervous system, CNS) NA activity leading to depression.
In addition to enhancing NA release, α2-adrenoceptor antagonism also increases serotonergic neurotransmission due to blockade of α2-adrenoceptors present on 5-HT nerve terminals.
Serotonergic
5-Hydroxytryptamine (5-HT or serotonin) is an important cell-to-cell signalling molecule found in all animal phyla. In mammals, substantial concentrations of 5-HT are present in the central and peripheral nervous systems, gastrointestinal tract and cardiovascular system. 5-HT is capable of exerting a wide variety of biological effects by interacting with specific membrane-bound receptors, and at least 13 distinct 5-HT receptor subtypes have been cloned and characterised. With the exception of the 5-HT3 receptor subtype, which is a transmitter-gated ion channel, 5-HT receptors are members of the 7-transmembrane G protein-coupled receptor superfamily. In humans, the serotonergic system is implicated in various physiological processes such as sleep-wake cycles, maintenance of mood, control of food intake and regulation of blood pressure. In accordance with this, drugs that affect 5-HT-containing cells or 5-HT receptors are effective treatments for numerous indications, including depression, anxiety, obesity, nausea, and migraine.
Because serotonin and the related hormone melatonin are involved in promoting sleep, they counterbalance the wake-promoting action of increased catecholaminergic neurotransmission. This is accounted for by the lethargic feel that some SSRIs can produce, although TCAs and antipsychotics can also cause lethargy albeit through different mechanisms.
Appetite suppression is related to 5-HT2C receptor activation as for example was reported for PAL-287 recently.
Activation of the 5-HT2C receptor has been described as “panicogen” by users of ligands for this receptor (e.g. mCPP). Antagonism of the 5-HT2C receptor is known to augment dopaminergic output. Although SSRIs with 5-HT2C antagonist actions were recommended for the treatment of depression, 5-HT2C receptor agonists were suggested for treating cocaine addiction since this would be anti-addictive. Nevertheless, the 5-HT2C is known to be rapidly downregulated upon repeated administration of an agonist agent, and is actually antagonised.
Azapirone-type drugs (e.g. buspirone), which act as 5-HT1A receptor agonists and partial agonists have been developed as anxiolytic agents that are not associated with the dependence and side-effect profile of the benzodiazepines. The hippocampal neurogenesis produced by various types of antidepressants, likewise, is thought to be mediated by 5-HT1A receptors. Systemic administration of a 5-HT1A agonist also induces growth hormone and adrenocorticotropic hormone (ACTH) release through actions in the hypothalamus.
Current Antidepressants
Most antidepressants on the market today target the monoaminergic system.
SSRIs
The most commonly prescribed class of antidepressants in the USA today are the selective serotonin reuptake inhibitors (SSRIs). These drugs inhibit the uptake of the neurotransmitter 5-HT by blocking the SERT, thus increasing its synaptic concentration, and have shown to be efficacious in the treatment of depression, however sexual dysfunction and weight gain are two very common side-effects that result in discontinuation of treatment.
Although many patients benefit from SSRIs, it is estimated that approximately 50% of depressive individuals do not respond adequately to these agents. Even in remitters, a relapse is often observed following drug discontinuation. The major limitation of SSRIs concerns their delay of action. It appears that the clinical efficacy of SSRIs becomes evident only after a few weeks.
SSRIs can be combined with a host of other drugs including bupropion, α2 adrenergic antagonists (e.g. yohimbine) as well as some of the atypical antipsychotics. The augmentation agents are said to behave synergistically with the SSRI although these are clearly of less value than taking a single compound that contains all of the necessary pharmacophoric elements relative to the consumption of a mixture of different compounds. It is not entirely known what the reason for this is, although ease of dosing is likely to be a considerable factor. In addition, single compounds are more likely to be approved by the FDA than are drugs that contain greater than one pharmaceutical ingredient (polytherapies).
A number of SRIs were under development that had auxiliary interactions with other receptors. Particularly notable were agents behaving as co-joint SSRIs with additional antagonist activity at 5-HT1A receptors. 5-HT1A receptors are located presynaptically as well as post-synaptically. It is the presynaptic receptors that are believed to function as autoreceptors (cf. studies done with pindolol). These agents were shown to elicit a more robust augmentation in the % elevation of extracellular 5-HT relative to baseline than was the case for SSRIs as measured by in vivo microdialysis.
NRIs
Norepinephrine reuptake inhibitors (NRIs) such as reboxetine prevent the reuptake of norepinephrine, providing a different mechanism of action to treat depression. However reboxetine is no more effective than the SSRIs in treating depression. In addition, atomoxetine has found use in the treatment of ADHD as a non-addictive alternative to Ritalin. The chemical structure of atomoxetine is closely related to that of fluoxetine (an SSRI) and also duloxetine (an SNRI).
NDRIs
Bupropion is a commonly prescribed antidepressant that acts as a norepinephrine–dopamine reuptake inhibitor (NDRI). It prevents the reuptake of NA and DA (weakly) by blocking the corresponding transporters, leading to increased noradrenergic and dopaminergic neurotransmission. This drug does not cause sexual dysfunction or weight gain like the SSRIs but has a higher incidence of nausea. Methylphenidate is a much more reliable example of an NDRI (the action that it displays on the DAT usually getting preferential treatment). Methylphenidate is used in the treatment of ADHD; its use in treating depression is not known to have been reported, but it is presumed owing to its psychomotor activating effects and it functioning as a positive reinforcer. There are also reports of methylphenidate being used in the treatment of psychostimulant addiction, in particular cocaine addiction, since the addictive actions of this drug are believed to be mediated by the dopamineneurotransmitter.
Sibutramine is the name of an SNRI based appetite suppressant with use in the treatment of obesity. This was explored in the treatment of depression, but was shown not to be effective.
Both sibutramine and venlafaxine are phenethylamine-based. At high doses, both venlafaxine and sibutramine will start producing dopaminergic effects. The inhibition of DA reuptake is unlikely to be relevant at clinically approved doses.
MAOIs
Monoamine oxidase inhibitors (MAOIs) were the first antidepressants to be introduced. They were discovered entirely by serendipity. Iproniazide (the first MAOI) was originally developed as an antitubercular agent but was then unexpectedly found to display antidepressant activity.
Isoniazid also displayed activity as an antidepressant, even though it is not a MAOI. This led some people to question whether it is some property of the hydrazine, which is responsible for mediating the antidepressant effect, even going as far as to state that the MAOI activity could be a secondary side-effect. However, with the discovery of tranylcypromine (the first non-hydrazine MAOI), it was shown that MAOI is thought to underlie the antidepressant bioactivity of these agents. Etryptamine is another example of a non-hydrazine MAOI that was introduced.
The MAOIs work by inhibiting the monoamine oxidase enzymes that, as the name suggests, break down the monoamine neurotransmitters. This leads to increased concentrations of most of the monoamine neurotransmitters in the human brain, serotonin, norepinephrine, dopamine and melatonin. The fact that they are more efficacious than the newer generation antidepressants is what leads scientists to develop newer antidepressants that target a greater range of neurotransmitters. The problem with MAOIs is that they have many potentially dangerous side-effects such as hypotension, and there is a risk of food and drug interactions that can result in potentially fatal serotonin syndrome or a hypertensive crisis. Although selective MAOIs can reduce, if not eliminate these risks, their efficacy tends to be lower.
MAOIs may preferentially treat TCA-resistant depression, especially in patients with features such as fatigue, volition inhibition, motor retardation and hypersomnia. This may be a function of the ability of MAOIs to increase synaptic levels of DA in addition to 5-HT and NE. The MAOIs also seem to be effective in the treatment of fatigue associated with fibromyalgia (FM) or chronic fatigue syndrome (CFS).
Although a substantial number of MAOIs were approved in the 1960s, many of these were taken off the market as rapidly as they were introduced. The reason for this is that they were hepatotoxic and could cause jaundice.
TCAs
The first tricyclic antidepressant (TCA), imipramine (Tofranil), was derived from the antipsychotic drug chlorpromazine, which was developed as a useful antihistaminergic agent with possible use as a hypnotic sedative. Imipramine is an iminodibenzyl (dibenzazepine).
The TCAs such as imipramine and amitriptyline typically prevent the reuptake of serotonin or norepinephine.
It is the histaminiergic (H1), muscarinic acetylcholinergic (M1), and alpha adrenergic (α1) blockade that is responsible for the side-effects of TCAs. These include somnolence and lethargy, anticholinergic side-effects, and hypotension. Due to the narrow gap between their ability to block the biogenic amine uptake pumps versus the inhibition of fast sodium channels, even a modest overdose of one of the TCAs could be lethal. TCAs were, for 25 years, the leading cause of death from overdoses in many countries. Patients being treated with antidepressants are prone to attempt suicide and one method they use is to take an overdose of their medications.
Another example of a TCA is amineptine which is the only one believed to function as a DRI. It is no longer available.
Failure of SNDRIs for Depression
SNDRIs have been under investigation for the treatment of major depressive disorder for a number of years but, as of 2015, have failed to meet effectiveness expectations in clinical trials. In addition, the augmentation of a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor with lisdexamfetamine, a norepinephrine–dopamine releasing agent, recently failed to separate from placebo in phase III clinical trials of individuals with treatment-resistant depression, and clinical development was subsequently discontinued. These occurrences have shed doubt on the potential benefit of dopaminergic augmentation of conventional serotonergic and noradrenergic antidepressant therapy. As such, scepticism has been cast on the promise of the remaining SNDRIs that are still being trialled, such as ansofaxine (currently in phase II trials), in the treatment of depression. Despite being a weak SNDRI, nefazodone has been successful in treating major depressive disorder.
5-HTTLPR (serotonin-transporter-linked promoter region) is a degenerate repeat (redundancy in the genetic code) polymorphic region in SLC6A4, the gene that codes for the serotonin transporter.
Since the polymorphism was identified in the middle of the 1990s, it has been extensively investigated, e.g., in connection with neuropsychiatric disorders. A 2006 scientific article stated that “over 300 behavioural, psychiatric, pharmacogenetic and other medical genetics papers” had analysed the polymorphism. While often discussed as an example of gene-environment interaction, this contention is contested.
Alleles
The polymorphism occurs in the promoter region of the gene. Researchers commonly report it with two variations in humans: A short (“s”) and a long (“l”), but it can be subdivided further. The short (s)- and long (l)- alleles have been thought to be related to stress and psychiatric disorders. In connection with the region are two single nucleotide polymorphisms (SNP): rs25531 and rs25532.
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 Europeans. The difference between 16-A and 16-D is the rs25531 SNP. It is also the difference between 14-A and 14-D.
Some studies have found that long allele results in higher serotonin transporter mRNA transcription in human cell lines. The higher level may be due to the A-allele of rs25531, such that subjects with the long-rs25531(A) allelic combination (sometimes written LA) have higher levels while long-rs25531(G) carriers have levels more similar to short-allele carriers. Newer studies examining the effects of genotype may compare the LA/LA genotype against all other genotypes. The allele frequency of this polymorphism seems to vary considerably across populations, with a higher frequency of the long allele in Europe and lower frequency in Asia. It is argued that the population variation in the allele frequency is more likely due to neutral evolutionary processes than natural selection.
Neuropsychiatric Disorders
In the 1990s it has been speculated that the polymorphism might be related to affective disorders, and an initial study found such a link. However, another large European study found no such link. A decade later two studies found that 5-HTT polymorphism influences depressive responses to life stress; an example of gene-environment interaction (GxE) not considered in the previous studies. However, a 2017 meta-analysis found no such association. Earlier, two 2009 meta-analyses found no overall GxE effect, while a 2011 meta-analysis, demonstrated a positive result. In turn, the 2011 meta-analysis has been criticised as being overly inclusive (e.g. including hip fractures as outcomes), for deeming a study supportive of the GxE interaction which is actually in the opposite direction, and because of substantial evidence of publication bias and data mining in the literature. This criticism points out that if the original finding were real, and not the result of publication bias, we would expect that those replication studies which are closest in design to the original are the most likely to replicate—instead we find the opposite. This suggests that authors may be data dredging for measures and analytic strategies which yield the results they want.
Treatment Response
With the results from one study the polymorphism was thought to be related to treatment response so that long-allele patients respond better to antidepressants. Another antidepressant treatment response study did, however, rather point to the rs25531 SNP, and a large study by the group of investigators found a “lack of association between response to an SSRI and variation at the SLC6A4 locus”.
Amygdala
The 5-HTTLPR has been thought to predispose individuals to affective disorders such as anxiety and depression. There have been some studies that test whether this association is due to the effects of variation in 5-HTTLPR on the reactivity of the human amygdala. In order to test this, researchers gathered a group of subjects and administered a harm avoidance (HA) subset of the Tridimensional Personality Questionnaire as an initial mood and personality assessment. Subjects also had their DNA isolated and analysed in order to be genotyped. Next, the amygdala was then engaged by having the subject match fearful facial expressions during an fMRI scan (by the 3-T GE Signa scanner). The results of the study showed that there was bilateral activity in the amygdala for every subject when processing the fearful images, as expected. However, the activity in the right amygdala was much higher for subjects with the s-allele, which shows that the 5-HTTLPR has an effect on amygdala activity. There did not seem to be the same effect on the left amygdala.
Insomnia
There has been speculation that the 5-HTTLPR gene is associated with insomnia and sleep quality. Primary insomnia is one of the most common sleep disorders and is defined as having trouble falling or staying asleep, enough to cause distress in one’s life. Serotonin (5-HT) has been associated with the regulation of sleep for a very long time now. The 5-HT transporter (5-HTT) is the main regulator of serotonin and serotonergic energy and is therefore targeted by many antidepressants. There also have been several family and twin studies that suggest that insomnia is heavily genetically influenced. Many of these studies have found that there is a genetic and environment dual-factor that influences insomnia. It has been hypothesized that the short 5-HTTLPR genotype is related to poor sleep quality and, therefore, also primary insomnia. It is important to note that research studies have found that this variation does not cause insomnia, but rather may predispose an individual to experience worse quality of sleep when faced with a stressful life event.
Brummett
The effect that the 5-HTTLPR gene had on sleep quality was tested by Brummett in a study conducted at Duke University Medical Centre from 2001 to 2004. The sleep quality of 344 participants was measured using The Pittsburgh Sleep Quality Index. The study found that caregivers with the homozygous s-allele had poorer sleep quality, which shows that the stress of caregiving combined with the allele gave way to worse sleep quality. Although the study found that the 5-HTTLPR genotype did not directly affect sleep quality, the 5-HTTLPR polymorphism’s effect on sleep quality was magnified by one’s environmental stress. It supports the notion that the 5-HTTLPR s-allele is what leads to hyperarousal when exposed to stress; hyperarousability is commonly associated with insomnia.
Deuschle
However, in a 2007 study conducted by a sleep laboratory in Germany, it was found that the 5-HTTLPR gene did have a strong association with both insomnia and depression both in participants with and without lifetime affective disorders. This study included 157 insomnia patients and a control group of 836 individuals that had no psychiatric disorders. The subjects were then genotyped through polymerase chain reaction (PCR) techniques. The researchers found that the s-allele was greater represented in the vast majority of patients with insomnia compared to those who had no disorder. This shows that there is an association between the 5-HTTPLR genotype and primary insomnia. However, it is important to consider the fact that there was a very limited number of subjects with insomnia tested in this study.
Personality Traits
5-HTTLPR may be related to personality traits: Two 2004 meta-analyses found 26 research studies investigating the polymorphism in relation to anxiety-related traits. The initial and classic 1996 study found s-allele carriers to on average have slightly higher neuroticism score with the NEO PI-R personality questionnaire, and this result was replicated by the group with new data. Some other studies have, however, failed to find this association, nor with peer-rated neuroticism, and a 2006 review noted the “erratic success in replication” of the first finding. A meta-analysis published in 2004 stated that the lack of replicability was “largely due to small sample size and the use of different inventories”. They found that neuroticism as measured with the NEO-family of personality inventories had quite significant association with 5-HTTLPR while the trait harm avoidance from the Temperament and Character Inventory family did not have any significant association. A similar conclusion was reached in an updated 2008 meta-analysis.] However, based on over 4000 subjects, the largest study that used the NEO PI-R found no association between variants of the serotonin transporter gene (including 5-HTTLPR) and neuroticism, or its facets (Anxiety, Angry-Hostility, Depression, Self-Consciousness, Impulsiveness, and Vulnerability).
In a study published in 2009, authors found that individuals homozygous for the long allele of 5-HTTLPR paid more attention on average to positive affective pictures while selectively avoiding negative affective pictures presented alongside the positive pictures compared to their heterozygous and short-allele-homozygous peers. This biased attention of positive emotional stimuli suggests they may tend to be more optimistic. Other research indicates carriers of the short 5-HTTLPR allele have difficulty disengaging attention from emotional stimuli compared to long allele homozygotes. Another study published in 2009 using an eye tracking assessment of information processing found that short 5-HTTLPR allele carriers displayed an eye gaze bias to view positive scenes and avoid negative scenes, while long allele homozygotes viewed the emotion scenes in a more even-handed fashion. This research suggests that short 5-HTTLPR allele carriers may be more sensitive to emotional information in the environment than long allele homozygotes.
Another research group have given evidence for a modest association between shyness and the long form in grade school children. This is, however, just a single report and the link is not investigated as intensively as for the anxiety-related traits.
Neuroimaging
Molecular neuroimaging studies have examined the association between genotype and serotonin transporter binding with positron emission tomography (PET) and SPECT brain scanners. Such studies use a radioligand that binds—preferably selectively—to the serotonin transporter so an image can be formed that quantifies the distribution of the serotonin transporter in the brain. One study could see no difference in serotonin transporter availability between long/long and short/short homozygotes subjects among 96 subjects scanned with SPECT using the iodine-123 β-CIT radioligand. Using the PET radioligand carbon-11-labeled McN 5652 another research team could neither find any difference in serotonin transporter binding between genotype groups. Newer studies have used the radioligand carbon-11-labeled DASB with one study finding higher serotonin transporter binding in the putamen of LA homozygotes compared to other genotypes. Another study with similar radioligand and genotype comparison found higher binding in the midbrain.
Associations between the polymorphism and the grey matter in parts of the anterior cingulate brain region have also been reported based on magnetic resonance imaging (MRI) brain scanning and voxel-based morphometry analysis. 5-HTTLPR short allele–driven amygdala hyperreactivity was confirmed in a large (by MRI study standards) cohort of healthy subjects with no history of psychiatric illness or treatment. Brain blood flow measurements with positron emission tomography brain scanners can show genotype-related changes. The glucose metabolism in the brain has also been investigated with respect to the polymorphism, and the functional magnetic resonance imaging (fMRI) brain scans have also been correlated to the polymorphism.
The amygdala brain structure has, especially, been the focus of the functional neuroimaging studies.
Electrophysiology
The relationship between the Event Related Potentials P3a and P3b and the genetic variants of 5-HTTLPR were investigated using an auditory oddball paradigm and revealed short allele homozygotes mimicked those of COMT met/met homozygotes with an enhancement of the frontal, but not parietal P3a and P3b. This suggests a frontal-cortical dopaminergic and serotoninergic mechanism in bottom-up attentional capture.
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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
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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A serotonin–dopamine reuptake inhibitor (SDRI) is a type of drug which acts as a reuptake inhibitor of the monoamine neurotransmitters serotonin and dopamine by blocking the actions of the serotonin transporter (SERT) and dopamine transporter (DAT), respectively. This in turn leads to increased extracellular concentrations of serotonin and dopamine, and, therefore, an increase in serotonergic and dopaminergic neurotransmission.
A closely related type of drug is a serotonin–dopamine releasing agent (SDRA).
Comparison to SNDRIs
Relative to serotonin–norepinephrine–dopamine reuptake inhibitors (SNDRIs), which also inhibit the reuptake of norepinephrine in addition to serotonin and dopamine, SDRIs might be expected to have a reduced incidence of certain side effects, namely insomnia, appetite loss, anxiety, and heart rate and blood pressure changes.
Examples of SDRIs
Unlike the case of other combination monoamine reuptake inhibitors such as serotonin–norepinephrine reuptake inhibitors (SNRIs) and norepinephrine–dopamine reuptake inhibitors (NDRIs), on account of the very similar chemical structures of their substrates, it is exceptionally difficult to tease apart affinity for the DAT from the norepinephrine transporter (NET) and inhibit the reuptake of dopamine alone. As a result, selective dopamine reuptake inhibitors (DRIs) are rare, and comparably, SDRIs are even more so.
Pharmaceutical Drugs
Medifoxamine (Cledial, Gerdaxyl) is an antidepressant that appears to act as an SDRI as well as a 5-HT2 receptor antagonist. Sibutramine (Reductil, Meridia, Siredia, Sibutrex) is a withdrawn anorectic that itself as a molecule in vitro is an SNDRI but preferentially an SDRI, with 18.3- and 5.8-fold preference for inhibiting the reuptake of serotonin and dopamine over norepinephrine, respectively. However, the metabolites of sibutramine are substantially more potent and possess different ratios of monoamine reuptake inhibition in comparison, and sibutramine appears to be acting in vivo mainly as a prodrug to them; accordingly, it was found to act as an SNRI (73% and 54% for norepinephrine and serotonin reuptake inhibition, respectively) in human volunteers with only very weak inhibition of dopamine reuptake (16%).
Sertraline
Sertraline (Zoloft) is a selective serotonin reuptake inhibitor (SSRI), but, uniquely among most antidepressants, it shows relatively high (nanomolar) affinity for the DAT as well. As such, it has been suggested that clinically it may weakly inhibit the reuptake of dopamine, particularly at high dosages. For this reason, sertraline has sometimes been described as an SDRI. This is relevant as dopamine is thought to be involved in the pathophysiology of depression, and increased dopaminergic signaling by sertraline in addition to serotonin may have additional benefits against depression.
Tatsumi et al. (1997) found Ki values of sertraline at the SERT, DAT, and NET of 0.29, 25, and 420 nM, respectively. The selectivity of sertraline for the SERT over the DAT was 86-fold. In any case, of the wide assortment of antidepressants assessed in the study, sertraline showed the highest affinity of them all for the DAT, even higher than the norepinephrine–dopamine reuptake inhibitors (NDRIs) nomifensine (Ki = 56 nM) and bupropion (Ki = 520 nM). Sertraline is also said to have similar affinity for the DAT as the NDRI methylphenidate. It is notable that tametraline (CP-24,441), a very close analogue of sertraline and the compound from which sertraline was originally derived, is an NDRI that was never marketed.
Single doses of 50 to 200 mg sertraline have been found to result in peak plasma concentrations of 20 to 55 ng/mL (65–180 nM), while chronic treatment with 200 mg/day sertraline, the maximum recommended dosage, has been found to result in maximal plasma levels of 118 to 166 ng/mL (385–542 nM). However, sertraline is highly protein-bound in plasma, with a bound fraction of 98.5%. Hence, only 1.5% is free and theoretically bioactive. Based on this percentage, free concentrations of sertraline would be 2.49 ng/mL (8.13 nM) at the very most, which is only about one-third of the Ki value that Tatsumi et al. found with sertraline at the DAT. A very high dosage of sertraline of 400 mg/day has been found to produce peak plasma concentrations of about 250 ng/mL (816 nM). This can be estimated to result in a free concentration of 3.75 ng/mL (12.2 nM), which is still only about half of the Ki of sertraline for the DAT.
As such, it seems unlikely that sertraline would produce much inhibition of dopamine reuptake even at clinically used dosages well in excess of the recommended maximum clinical dosage. This is in accordance with its 86-fold selectivity for the SERT over the DAT and hence the fact that nearly 100-fold higher levels of sertraline would be necessary to also inhibit dopamine reuptake. In accordance, while sertraline has very low abuse potential and may even be aversive at clinical dosages, a case report of sertraline abuse described dopaminergic-like effects such as euphoria, mental overactivity, and hallucinations only at a dosage 56 times the normal maximum and 224 times the normal minimum. For these reasons, significant inhibition of dopamine reuptake by sertraline at clinical dosages is controversial, and occupation by sertraline of the DAT is thought by many experts to not be clinically relevant.
Research Chemicals
Two SDRIs that are known in research at present are RTI-83 and UWA-101, though other related compounds are also known. Based on its chemical structure, UWA-101 may actually also possess some activity as a releasing agent, and if so, unlike RTI-83, it would not be an SDRI in the purest sense and would also be an SDRA. Manning et al. presented two high-affinity MAT-ligands with good binding selectivity for SERT and DAT, namely the 4-indolyl and 1-naphthyl arylalkylamines ent-16b (Ki 0.82, 3.8, 4840 nM for SERT, DAT, NET) and ent-13b respectively. AN-788 (NSD-788) is another SDRI, and has been under development for the treatment of depressive and anxiety disorders.
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A norepinephrine–dopamine reuptake inhibitor (NDRI) is a drug used for the treatment of clinical depression, attention deficit hyperactivity disorder (ADHD), narcolepsy, and the management of Parkinson’s disease. The drug acts as a reuptake inhibitor for the neurotransmittersnorepinephrine and dopamine by blocking the action of the norepinephrine transporter (NET) and the dopamine transporter (DAT), respectively. This in turn leads to increased extracellular concentrations of both norepinephrine and dopamine and, therefore, an increase in adrenergic and dopaminergic neurotransmission.
The section only lists compounds that are selective for NET and DAT relative to the serotonin transporter (SERT). For a list of compounds that inhibit reuptake at all three transporters, see serotonin–norepinephrine–dopamine reuptake inhibitor.
Amphetamine and many of its immediate derivatives (i.e., the substituted amphetamines) are also both non-competitive and competitive inhibitors of the dopamine transporter (DAT), norepinephrine transporter (NET), and serotonin transporter (SERT) proteins. Amphetamine itself has comparatively low affinity for SERT relative to DAT and NET. Consequently, amphetamine is usually classified as an NDRI instead of an SNDRI. However, the substituted amphetamines have a very diverse effects profile, and many of them have significant inhibiting effects on the SERT.
Amphetamine and many of the other substituted amphetamines are inhibitors of VMAT2 and potent agonists of the trace amine-associated receptor 1 (TAAR1); agonism of TAAR1 triggers phosphorylation events that result in both non-competitive reuptake inhibition and reversed transport direction of monoamine transporter proteins. As a result, monoamines flow out of the cell and into the synaptic cleft. Thus, amphetamine and its derivatives have a pharmacological profile that is much different than classical NDRIs, but analogous to trace amines.
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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.
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