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80-673: The plasma membrane monoamine transporter ( PMAT ) is a low-affinity monoamine transporter protein which in humans is encoded by the SLC29A4 gene . It is known alternatively as the human equilibrative nucleoside transporter-4 (hENT4). It was discovered in 2004 and has been identified as a potential alternate target for treating various conditions. 222962 243328 ENSG00000164638 ENSMUSG00000050822 Q7RTT9 Q8R139 NM_001040661 NM_001300847 NM_153247 NM_146257 NP_001035751 NP_001287776 NP_694979 NP_666369 The plasma membrane monoamine transporter

160-503: A non-selective reuptake inhibitor . Methylphenidate is not an inhibitor of SERT. It has been observed that the pathology of depression involves dysfunction of monoamine neurotransmitter circuits in the CNS, particularly of serotonin and norepinephrine. Selective serotonin reuptake inhibitors (SSRIs) are the most widely used antidepressant and include fluoxetine (Prozac), citalopram (Celexa), and fluvoxamine (Luvox). These drugs inhibit

240-459: A triptan for migraine does not appear to heighten the risk of the serotonin syndrome. Taking monoamine oxidase inhibitors (MAOIs) in combination with SSRIs can be fatal, since MAOIs disrupt monoamine oxidase , an enzyme which is needed to break down serotonin and other neurotransmitters. Without monoamine oxidase, the body is unable to eliminate excess neurotransmitters, allowing them to build up to dangerous levels. The prognosis for recovery in

320-573: A "high risk of bias", but agreed with the EMA assessment that cautionary labeling on SSRIs was warranted. On the 20th of march of 2024, a lawsuit was filed by the organization Public Citizen , representing Dr. Antonei Csoka , against the United States Food and Drug Administration (FDA) for failing to act on a citizen petition submitted in 2018. The petition seeks to have the risk of serious sexual side effects persisting after discontinuation mentioned in

400-837: A 10-week randomized controlled, double-blind trial escitalopram was more effective than placebo. Fluvoxamine , another SSRI, has shown positive results. However, evidence for their effectiveness and acceptability is unclear. Antidepressants are recommended as an alternative or additional first step to self-help programs in the treatment of bulimia nervosa . SSRIs (fluoxetine in particular) are preferred over other anti-depressants due to their acceptability, tolerability, and superior reduction of symptoms in short-term trials. Long-term efficacy remains poorly characterized. Similar recommendations apply to binge eating disorder . SSRIs provide short-term reductions in binge eating behavior, but have not been associated with significant weight loss. Clinical trials have generated mostly negative results for

480-521: A 2004 U.S. Food and Drug Administration (FDA) analysis of clinical trials on children with major depressive disorder found statistically significant increases of the risks of "possible suicidal ideation and suicidal behavior" by about 80%, and of agitation and hostility by about 130%. According to the FDA, the heightened risk of suicidality is within the first one to two months of treatment. The National Institute for Health and Care Excellence (NICE) places

560-498: A 2023 study a possible connection between SSRI usage and the onset of mitral valve regurgitation was identified, indicating that SSRIs could hasten the progression of degenerative mitral valve regurgitation (DMR), especially in individuals carrying 5-HTTLPR genotype. The study’s authors suggest that genotyping should be performed on people with DMR to evaluate serotonin transporter (SERT) activity. They also urge practitioners to exercise caution when prescribing SSRIs to individuals with

640-415: A daily basis is consistent with clinical observations that the therapeutic effects of SSRIs generally take several weeks to emerge. Sexual dysfunction ranging from decreased libido to anorgasmia is usually considered to be a significantly distressing side effect which may lead to noncompliance in patients receiving SSRIs. However, for those with premature ejaculation, this very same side effect becomes

720-421: A decrease in bone mineral density, as well as increased fracture risk, a relationship that appears to persist even with adjuvant bisphosphonate therapy. However, because the relationship between SSRIs and fractures is based on observational data as opposed to prospective trials, the phenomenon is not definitively causal. There also appears to be an increase in fracture-inducing falls with SSRI use, suggesting

800-401: A familial history of DMR. SSRIs directly increase the risk of abnormal bleeding by lowering platelet serotonin levels, which are essential to platelet-driven hemostasis. SSRIs interact with anticoagulants , like warfarin , and antiplatelet drugs , like aspirin . This includes an increased risk of GI bleeding , and post operative bleeding. The relative risk of intracranial bleeding

880-451: A favorable risk-benefit ratio in children with depression, though it was also associated with a slight increase in the risk of self-harm and suicidal ideation. Only two SSRIs are licensed for use with children in the UK, sertraline (Zoloft) and fluvoxamine (Luvox), for the treatment of obsessive–compulsive disorder . Fluoxetine is not licensed for this use. It is unclear whether SSRIs affect

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960-465: A functional DAT is necessary which suggests that DAT dysfunction may contribute to schizophrenia. DAT is also the target of several "DAT-blockers" including amphetamine and cocaine . These chemicals inhibit the action of DAT and, to a lesser extent, the other monoamine transporters, but their effects are mediated by separate mechanisms. Monoamine transporters are established targets for many pharmacological agents that affect brain function, including

1040-428: A hospital setting is generally good if serotonin syndrome is correctly identified. Treatment consists of discontinuing any serotonergic drugs and providing supportive care to manage agitation and hyperthermia , usually with benzodiazepines . Meta analyses of short duration randomized clinical trials have found that SSRI use is related to a higher risk of suicidal behavior in children and adolescents. For instance,

1120-626: A net efflux of substrates and ions out of a neuron. To return to an outwardly facing conformation SERT requires the transport of intracellular K . There is no evidence that the other transporters have such a requirement. Phosphorylation plays a key role in MAT function. When SERT is phosphorylated by the PKC-dependent pathway SERT internalization occurs. The internalization of SERT reduces 5-HT uptake. Similar phosphorylation events occur in DAT and NET, decreasing

1200-486: A number of existing compounds have been found to act as weak inhibitors of this transporter, with the exception of decynium-22 , which is more potent. These compounds include: Lopinavir shows promising results as a newly discovered selective PMAT inhibitor that does not impact. This membrane protein –related article is a stub . You can help Misplaced Pages by expanding it . Monoamine transporter There are several different monoamine transporters located along

1280-846: A potential glycosylation site, and its first 6 transmembrane domains are suspected to be important for substrate recognition. It is not homologous to other known monoamine transporters, such as the high-affinity SERT, DAT, and NET, or the low-affinity SLC22A OCT family. It was initially identified by a search of the draft human genome database through its sequence homology to ENTs (equilibrative nucleoside transporters). Common SSRIs have been shown to inhibit PMAT uptake but at far greater concentrations than SERT. Residual uptake due to incomplete inhibition of PMAT may contribute to SSRI treatment resistance. Mice models with specific constitutive genetic deficiencies in PMAT have demonstrated behavioral changes relative to WT, including upon anti-depressant administration. PMAT

1360-450: A reduction or loss of sensitivity in the genitals or other erogenous zones . Additional non-sexual symptoms are also commonly described, including emotional numbing , anhedonia , depersonalization or derealization , and cognitive impairment . The duration of PSSD symptoms appears to vary among patients, with some cases resolving in months and others in years or decades; one analysis of patient reports submitted between 1992 and 2021 in

1440-668: A set of symptoms reported by some people who have taken SSRIs or other serotonin reuptake-inhibiting (SRI) drugs, in which sexual dysfunction symptoms persist for at least three months after ceasing to take the drug. The status of PSSD as a legitimate and distinct pathology is contentious; several researchers have proposed that it should be recognized as a separate phenomenon from more common SSRI side effects. The reported symptoms of PSSD include reduced sexual desire or arousal , erectile dysfunction in males or loss of vaginal lubrication in females, difficulty having an orgasm or loss of pleasurable sensation associated with orgasm, and

1520-468: A small and unimportant way compared with placebo." However, it also noted significant methodological limitations that make drawing definitive conclusions about efficacy difficult. Fluoxetine is the only SSRI authorized for use in children and adolescents with moderate to severe depression in the United Kingdom . Some SSRIs are effective for social anxiety disorder, although their effects on symptoms

1600-471: Is a common disorder of which the central feature is excessive worry about a number of different events. Key symptoms include excessive anxiety about multiple events and issues, and difficulty controlling worrisome thoughts, that persists for at least 6 months. Antidepressants provide a modest-to-moderate reduction in anxiety in GAD, and are superior to placebo in treating GAD. The efficacy of different antidepressants

1680-625: Is also associated with preterm birth . According to some researches, decreased body weight of the child, intrauterine growth retardation, neonatal adaptive syndrome, and persistent pulmonary hypertension also was noted. A systematic review of the risk of major birth defects in antidepressant-exposed pregnancies found a small increase (3% to 24%) in the risk of major malformations and a risk of cardiovascular birth defects that did not differ from non-exposed pregnancies. Other studies have found an increased risk of cardiovascular birth defects among depressed mothers not undergoing SSRI treatment, suggesting

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1760-419: Is an antidepressant drug that is a relatively selective inhibitor of NE uptake. Studies of inhibition of NET correlate with antidepressant activity. NET regulation is linked to altered dopamine transmission and schizophrenia-like behaviors. Nisoxetine is a NET inhibitor and reverses some schizophrenia-linked behavior. NET activities regulate NE as well as DA equilibrium. In addition, for normal DA clearance

1840-440: Is an integral membrane protein that transports the monoamine neurotransmitters ( serotonin , dopamine , norepinephrine ) as well as adenosine , from synaptic spaces into presynaptic neurons or neighboring glial cells . It is abundantly expressed in the human brain, heart tissue, and skeletal muscle, as well as in the kidneys, liver, and small intestine. It is relatively insensitive to the high affinity inhibitors (such as SSRIs) of

1920-466: Is attempting to clarify the extent to which kinase cascades, transporter interacting proteins, and phosphorylation contribute to MAT regulation. Below are examples of drugs that act directly by inhibiting two or more MATs simultaneously. Serotonin-norepinephrine re-uptake inhibitors ( SNRIs ) act by blocking both SERTs and NETs. Triple re-uptake inhibitors ( TRIs ) act by blocking DATs, NETs, and SERTs simultaneously. Most modern antidepressant drugs work on

2000-401: Is available to determine whether there are long-term effects. Persistent pulmonary hypertension (PPHN) is a serious and life-threatening, but very rare, lung condition that occurs soon after birth of the newborn. Newborn babies with PPHN have high pressure in their lung blood vessels and are not able to get enough oxygen into their bloodstream. About 1 to 2 babies per 1000 babies born in

2080-461: Is effective. The mechanism by which SRIs may induce PSSD is unclear; neurobiological and cognitive factors may act in combination to cause the problem. As of 2023, prevalence is unknown. A 2020 review stated that PSSD is rare, underreported, and "increasingly identified in online communities". A 2024 study investigating the prevalence of persistent post-treatment genital numbness among sexual and gender minority youth found 13.2% of SSRI users between

2160-484: Is increased, but the absolute risk is very low. SSRIs are known to cause platelet dysfunction. This risk is greater in those who are also on anticoagulants, antiplatelet agents and NSAIDs (nonsteroidal anti-inflammatory drugs), as well as with the co-existence of underlying diseases such as cirrhosis of the liver or liver failure. Evidence from longitudinal, cross-sectional, and prospective cohort studies suggests an association between SSRI usage at therapeutic doses and

2240-450: Is independently associated with negative pregnancy outcomes, determining the extent to which observed associations between antidepressant use and specific adverse outcomes reflects a causative relationship has been difficult in some cases. In other cases, the attribution of adverse outcomes to antidepressant exposure seems fairly clear. SSRI use in pregnancy is associated with an increased risk of spontaneous abortion of about 1.7-fold. Use

2320-427: Is no agreement on standards for diagnosis. It is considered a distinct phenomenon from antidepressant discontinuation syndrome , post-acute withdrawal syndrome , and major depressive disorder , and should be distinguished from sexual dysfunction associated with depression and persistent genital arousal disorder . There are limited treatment options for PSSD as of 2023 and no evidence that any individual approach

2400-504: Is not always robust and their use is sometimes rejected in favor of psychological therapies. Paroxetine was the first drug to be approved for social anxiety disorder and it is considered effective for this disorder; sertraline and fluvoxamine were later approved for it as well. Escitalopram and citalopram are used off-label with acceptable efficacy, while fluoxetine is not considered to be effective for this disorder. The effect sizes ( Cohen's d ) of SSRIs in terms of improvement on

2480-440: Is one of the most common reasons people stop the medication. The mechanism by which SSRIs may cause sexual side effects is not well understood as of 2021 . The range of possible mechanisms includes (1) nonspecific neurological effects (e.g., sedation) that globally impair behavior including sexual function; (2) specific effects on brain systems mediating sexual function; (3) specific effects on peripheral tissues and organs, such as

Plasma membrane monoamine transporter - Misplaced Pages Continue

2560-508: Is permeable to in a highly pH-dependent manner. In addition to transporting neurotransmitters at synapses, PMAT plays a key role in neurotoxin and drug removal from the cerebrospinal fluid . It is also likely to play a key role in histamine clearance from synapses, specifically through astrocytes. PMAT has 530 amino acid residues with a predicted molecular weight of 58kD, 11 transmembrane segments, an extracellular C-terminus, and an intracellular N-terminus. It has several phosphorylation sites and

2640-491: Is possible that PMAT along with standard DAT inhibition could lead to better treatment outcomes with more complete blockage of uptake. PMAT is expressed within the apical membranes of enterocytes in the small intestine. Gene variants affecting the expression of PMAT have been demonstrated to increase the occurrence of GI disturbance side effects with metformin administration, the most common type II diabetes medication. No highly selective PMAT inhibitors are yet available, but

2720-524: Is similar. In Canada, SSRIs are a first-line treatment of adult obsessive–compulsive disorder (OCD). In the UK, they are first-line treatment only with moderate to severe functional impairment and as second line treatment for those with mild impairment, though, as of early 2019, this recommendation is being reviewed. In children, SSRIs can be considered a second line therapy in those with moderate-to-severe impairment, with close monitoring for psychiatric adverse effects. SSRIs, especially fluvoxamine , which

2800-411: Is the first one to be FDA approved for OCD, are efficacious in its treatment; patients treated with SSRIs are about twice as likely to respond to treatment as those treated with placebo. Efficacy has been demonstrated both in short-term treatment trials of 6 to 24 weeks and in discontinuation trials of 28 to 52 weeks duration. Paroxetine CR was superior to placebo on the primary outcome measure. In

2880-406: Is typically caused by the use of two or more serotonergic drugs, including SSRIs. Serotonin syndrome is a condition that can range from mild (most common) to deadly. Mild symptoms may consist of increased heart rate , fever , shivering, sweating , dilated pupils , myoclonus (intermittent jerking or twitching), as well as hyperreflexia . Concomitant use of SSRIs or SNRIs for depression with

2960-610: Is used off-label, but with mixed results; venlafaxine, an SNRI, is considered somewhat effective, although its use is also off-label. Fluvoxamine, escitalopram and citalopram are not well tested in this disorder. Paroxetine remains the most suitable drug for PTSD as of now, but with limited benefits. SSRIs are recommended by the National Institute for Health and Care Excellence (NICE) for the treatment of generalized anxiety disorder (GAD) that has failed to respond to conservative measures such as education and self-help activities. GAD

3040-487: The GABA transporter . Current research is underway to understand how MATs function and are regulated by looking at newly discovered structural and functional domains of these proteins. Over the last decade, the availability of targeted disruption of monoamine transporter genes in animal models as well as in vivo imaging approaches have shown progress in studies associated with psychiatric and movement disorders. Ongoing research

3120-582: The Liebowitz social anxiety scale in individual published trials of the drugs for social anxiety disorder have ranged from –0.029 to 1.214. PTSD is relatively hard to treat and generally treatment is not highly effective; SSRIs are no exception. They are not very effective for this disorder and only two SSRI are FDA approved for this condition: paroxetine and sertraline. Paroxetine has slightly higher response and remission rates for PTSD than sertraline, but both are not fully effective for many patients. Fluoxetine

3200-497: The Netherlands listed a case which had reportedly persisted for 23 years. The symptoms of PSSD are largely shared with post-finasteride syndrome (PFS) and post-retinoid sexual dysfunction (PRSD) , two other poorly-understood conditions which have been suggested to share a common etiology with PSSD despite being associated with different types of medication. Diagnostic criteria for PSSD were proposed in 2022, but as of 2023, there

3280-624: The cerebral cortex , CA1 and CA3 regions of the hippocampus, as well as the median and dorsal raphe nuclei . In the PNS, SERT is localized to the intestinal tract, adrenal glands , placenta, lung, and platelets . Expression of SERT in platelets is used as a means to reacquire 5-HT from the extracellular environment and later used in platelet activation. Regulation of SERT has been linked to acute depletion of intracellular Ca Na , calmodulin inhibition, CaMKII, Src , p38 MAP kinase , PKC, and activation of NOS / cGMP . Monoamine transporters are members of

Plasma membrane monoamine transporter - Misplaced Pages Continue

3360-450: The extracellular level of the neurotransmitter serotonin by limiting its reabsorption (reuptake) into the presynaptic cell . They have varying degrees of selectivity for the other monoamine transporters , with pure SSRIs having strong affinity for the serotonin transporter and only weak affinity for the norepinephrine and dopamine transporters . SSRIs are the most widely prescribed antidepressants in many countries especially

3440-449: The hippocampus and cortex. Peripherally, NET can be found in sympathetic peripheral neurons, the adrenal medulla , the lung, the placenta, and the vas deferens . Regulation of NET has been linked to MAPKs , insulin , PKC, and angiotensin II . SERT is responsible for the reuptake of extracellular serotonin (5-HT) in a Na /Cl -dependent process. In the CNS, SERT is found localized in

3520-497: The plasma membrane , each belonging to the family of Na /Cl -dependent substrate-specific neuronal membrane transporters. DAT is responsible for the Na /Cl -dependent reuptake of extracellular dopamine (DA). DATs can be found in the central nervous system (CNS), where they are localized in the substantia nigra and ventral tegmental area (VTA). DATs are also found in the peripheral nervous system ( PNS ) where they are localized in

3600-581: The EMA assessment, a safety review by Health Canada "could neither confirm nor rule out a causal link   ... which was long lasting in rare cases", but recommended that "healthcare professionals inform patients about the potential risk of long-lasting sexual dysfunction despite discontinuation of treatment". A 2023 review stated that ongoing sexual dysfunction after SSRI discontinuation was possible, but that cause and effect were undetermined. The 2023 review cautioned that reports of sexual dysfunction cannot be generalized to wider practice as they are subject to

3680-453: The SLC6A monoamine transporters (SERT, DAT, NET), as well being only weakly sensitive to the adenosine transport inhibitor, dipyridamole . PMAT is especially prevalent in dendrites with dense monoaminergic input, and has a significant impact on synaptic clearance of monoamines, especially under non-homeostatic conditions. PMAT transport is electrogenic, utilizing the naturally negative interior of

3760-560: The U.S. develop PPHN shortly after birth, and often they need intensive medical care . It is associated with about a 25% risk of significant long-term neurological deficits. A 2014 meta analysis found no increased risk of persistent pulmonary hypertension associated with exposure to SSRI's in early pregnancy and a slight increase in risk associates with exposure late in pregnancy; "an estimated 286 to 351 women would need to be treated with an SSRI in late pregnancy to result in an average of one additional case of persistent pulmonary hypertension of

3840-712: The UK National Institute for Health and Care Excellence (NICE) as a first-line treatment of severe depression and for the treatment of mild-to-moderate depression that persists after conservative measures such as cognitive therapy . They recommend against their routine use by those who have chronic health problems and mild depression. There has been controversy regarding the efficacy of SSRIs in treating depression depending on its severity and duration. The use of SSRIs in children with depression remains controversial. A 2021 Cochrane review concluded that, for children and adolescents, SSRIs "may reduce depression symptoms in

3920-609: The ages 15 and 29 reporting the symptom compared to 0.9% who had used other medications. Reports of PSSD have occurred with almost every SSRI ( dapoxetine is an exception). In 2019, the Pharmacovigilance Risk Assessment Committee of the European Medicines Agency (EMA) recommended that packaging leaflets of selected SSRIs and SNRIs should be amended to include information regarding a possible risk of persistent sexual dysfunction. Following

4000-413: The cells to attract the cationic monoamines, thereby increasing its V max (without changing affinity) with increasingly negative membrane potentials. PMAT preferentially transports 5-HT and DA, with a transport efficiency comparable to SERT and DAT, but a with a lower K m . PMAT and similar transporters like OCT3 are commonly referred to as uptake 2 transporters. Uptake 2 transport refers to

4080-487: The cells transport capacity of MAs. Monoamine transporters are believed to be factors in several neurological conditions due to their role in reuptake of the monoamines dopamine, noradrenaline, and serotonin. These conditions include ADHD , depression , drug abuse , Parkinson's disease , schizophrenia , and Tourette's syndrome . Evidence supporting this belief includes that monoamine transporters, DAT, NET, and SERT, are important target sites for therapeutic drugs used in

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4160-452: The desired effect . SSRIs such as sertraline have been found to be effective in decreasing anger . Side effects vary among the individual drugs of this class. They may include akathisia . SSRIs can cause various types of sexual dysfunction such as anorgasmia , erectile dysfunction , diminished libido , genital numbness, and sexual anhedonia (pleasureless orgasm). Sexual problems are common with SSRIs. Poor sexual function

4240-702: The excess risk in the "early stages of treatment". The European Psychiatric Association places the excess risk in the first two weeks of treatment and, based on a combination of epidemiological, prospective cohort, medical claims, and randomized clinical trial data, concludes that a protective effect dominates after this early period. A 2014 Cochrane review found that at six to nine months, suicidal ideation remained higher in children treated with antidepressants compared to those treated with psychological therapy. A recent comparison of aggression and hostility occurring during treatment with fluoxetine to placebo in children and adolescents found that no significant difference between

4320-477: The fluoxetine group and a placebo group. There is also evidence that higher rates of SSRI prescriptions are associated with lower rates of suicide in children, though since the evidence is correlational , the true nature of the relationship is unclear. In 2004, the Medicines and Healthcare products Regulatory Agency (MHRA) in the United Kingdom judged fluoxetine (Prozac) to be the only antidepressant that offered

4400-593: The group of Na /Cl -dependent substrate-specific neuronal membrane transporters belonging to the SLC6 gene family. MATs are large integral membrane proteins composed of 12 transmembrane domains connected by intracellular and extracellular loops. The NH 2 and COOH termini of the MAT proteins are located within the cytoplasm of presynaptic cells. All MATs contain sites for protein kinase phosphorylation by cAMP -dependent protein kinase, protein kinase C (PKC) and Ca /calmodulin-dependent protein kinase. MATs are responsible for

4480-601: The hyperactivity, inattention, and impulsivity in ADHD is related to abnormal DAT function and regulation. Dopaminergic hypofunction in the frontal cortex and basal ganglia is a neurobiological feature observed in ADHD. Psychostimulants that potently inhibit DAT, such as methylphenidate and amphetamine , are efficacious in treating ADHD. Methylphenidate (Ritalin) inhibits both DAT and NET, which results in an increase in extracellular dopamine and norepinephrine that can readily bind postsynaptic cells. Methylphenidate targets DAT as

4560-562: The increase in extracellular dopamine. In contrast, amphetamine enters the presynaptic neuron directly through the neuronal membrane or through monoamine transporters, competing for reuptake with neurotransmitters. Once inside, it binds to TAAR1 or enters synaptic vesicles through VMAT2 . When amphetamine binds to TAAR1, it reduces post-synaptic receptor firing rate and triggers protein kinase A and protein kinase C signaling, resulting in transporter phosphorylation. Phosphorylated transporters then either operate in reverse or withdraw into

4640-424: The medication, or switching to a different antidepressant that may have less propensity for causing this side effect. Acute narrow-angle glaucoma is the most common and important ocular side effect of SSRIs, and often goes misdiagnosed. SSRIs do not appear to affect the risk of coronary heart disease (CHD) in those without a previous diagnosis of CHD. A large cohort study suggested no substantial increase in

4720-404: The need for increased attention to fall risk in elderly patients using the medication. The loss of bone density does not appear to occur in younger patients taking SSRIs. SSRI and SNRI antidepressants may cause jaw pain/jaw spasm reversible syndrome (although it is not common). Buspirone appears to be successful in treating bruxism on SSRI/SNRI induced jaw clenching. Serotonin syndrome

4800-444: The penis, that mediate sexual function; and (4) direct or indirect effects on hormones mediating sexual function. Management strategies include: for erectile dysfunction the addition of a PDE5 inhibitor such as sildenafil ; for decreased libido, possibly adding or switching to bupropion ; and for overall sexual dysfunction, switching to nefazodone . Buspirone is sometimes used off-label to reduce sexual dysfunction associated with

4880-410: The pharmacological and functional properties of MAT proteins have been essential in the discovery of therapeutic treatment of many mental disorders. During the 1990s various cloning techniques using MATs have elucidated the genetic structure of these proteins. In 1991 Susan Amara and her colleagues determined the amino acid sequence of NET, discovering its relatively high coding similarities to that of

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4960-468: The possibility of ascertainment bias, e.g. that worried mothers may pursue more aggressive testing of their infants. Another study found no increase in cardiovascular birth defects and a 27% increased risk of major malformations in SSRI exposed pregnancies. The FDA issued a statement on July 19, 2006, stating nursing mothers on SSRIs must discuss treatment with their physicians. However, the medical literature on

5040-531: The presynaptic neuron and cease transport. When amphetamine enters the synaptic vesicles through VMAT2, monoamines are released into the cytosol. The field of monoamine transporter research began roughly five decades ago with Julius Axelrod 's research on NETs. Axelrod eventually received his Nobel Prize for this research, which led to the discovery of DATs and SERTs as well as consequences associated with antidepressant and psychostimulant interactions with MAT proteins. Since Axelrod's initial studies, understanding

5120-460: The principle of blocking re-uptake transporters. SSRI's such as Fluoxetine (Prozac) and SNRI's as with Venlafaxine are the main types of drugs given in first line depression and anxiety treatment. SSRIs Selective serotonin reuptake inhibitors ( SSRIs ) are a class of drugs that are typically used as antidepressants in the treatment of major depressive disorder , anxiety disorders , and other psychological conditions. SSRIs increase

5200-695: The product labels of SSRIs and SNRIs. Certain antidepressants may cause emotional blunting , characterized by reduced intensity of both positive and negative emotions as well as symptoms of apathy , indifference , and amotivation . It may be experienced as either beneficial or detrimental depending on the situation. This side effect has been particularly associated with serotonergic antidepressants like SSRIs and SNRIs, but may be less with atypical antidepressants like bupropion , agomelatine , and vortioxetine . Higher doses of antidepressants seem to be more likely to produce emotional blunting than lower doses. It can be decreased by reducing dosage, discontinuing

5280-501: The psychostimulants cocaine and amphetamine . Cocaine and amphetamine employ different mechanisms that both result in an increase in extracellular monoamines by decreasing reuptake. Psychostimulants affect primarily DAT, although there is some inhibition at SERT and NET. A large increase of synaptic dopamine results in an increased stimulation of target neurons believed to create the sensations of cocaine. The stimulatory and euphoric effects of cocaine are created when cocaine inhibits

5360-443: The reuptake of dopamine by DAT, which results in an increase in extracellular dopamine. Dopamine can then more readily bind neurons, which overstimulates the cells. Cocaine is a non-selective, competitive inhibitor of monoamine transporters, sharing a similar mechanism with that of methylphenidate . Cocaine interacts with DAT, SERT, and NET, although the behavioral and reinforcing effects of cocaine depend on its inhibition of DAT and

5440-415: The reuptake of serotonin from the extracellular space into the synaptic terminal by selectively inhibiting SERT. It has been recently observed that serotonin, norepinephrine, and dopamine may all be involved in depression. Therefore, drugs such as venlafaxine and paroxetine are being used as effective antidepressants that selectively inhibit both SERT and NET. The tricyclic antidepressant desipramine

5520-643: The risk of cardiac malformations attributable to SSRI usage during the first trimester of pregnancy. A number of large studies of people without known pre-existing heart disease have reported no EKG changes related to SSRI use. The recommended maximum daily dose of citalopram and escitalopram was reduced due to concerns with QT prolongation . In overdose, fluoxetine has been reported to cause sinus tachycardia , myocardial infarction , junctional rhythms , and trigeminy . Some authors have suggested electrocardiographic monitoring in patients with severe pre-existing cardiovascular disease who are taking SSRIs. In

5600-462: The risk of suicidal behavior in adults. A 2017 meta-analysis found that antidepressants including SSRIs were associated with significantly increased risk of death (+33%) and new cardiovascular complications (+14%) in the general population. Conversely, risks were not greater in people with existing cardiovascular disease . SSRI use in pregnancy has been associated with a variety of risks with varying degrees of proof of causation. As depression

5680-413: The safety of SSRIs has determined that some SSRIs like Sertraline and Paroxetine are considered safe for breastfeeding. Several studies have documented neonatal abstinence syndrome , a syndrome of neurological, gastrointestinal, autonomic, endocrine and/or respiratory symptoms among a large minority of infants with intrauterine exposure. These syndromes are short-lived, but insufficient long-term data

5760-453: The stomach, pancreas, as well as in lymphocytes . Various kinases have been linked to DAT regulation including PKA , PKC , PI-3K , ERK1 , ERK2 , Akt , CaMKII , CDK5 , and MAPK . NET is responsible for the Na /Cl -dependent reuptake of extracellular norepinephrine (NE). NET can also reuptake extracellular DA. Within the CNS, NET is localized to the dendrites and axons found in both

5840-479: The transport of biogenic amines through low affinity, high-capacity transporters. At low a pH, (5.5-6.5 range, as occurs under ischemic conditions) its transport efficiency increases for all substrates, whereas at high pH (>8) transport is blocked. Unlike other members of the ENT family, it is impermeable to most nucleosides , with the exception of the inhibitory neurotransmitter and ribonucleoside adenosine , which it

5920-465: The treatment of stroke patients, including those with and without symptoms of depression. A 2021 meta-analysis of randomized controlled clinical trials found no evidence pointing to their routine use to promote recovery following stroke. SSRIs are effective for the treatment of premature ejaculation. Taking SSRIs on a chronic, daily basis is more effective than taking them prior to sexual activity. The increased efficacy of treatment when taking SSRIs on

6000-492: The treatment of mood disorders. Several drugs are used to treat disease symptoms by blocking monoamine transporters, which results in an increase in extracellular monoamines. In addition, the levels of monoamine transporters have been shown to be altered in many of these psychiatric and neurological conditions. Finally, polymorphic variations in monoamine transporter genes have been proposed to be associated with conditions such as ADHD and depression. It has been observed that

6080-588: The uptake of monoamines by the sequential binding and co-transport of Na and Cl ions. The ion concentration gradient generated by the plasma membrane Na /K ATPase provides the driving force for the transporter-mediated monoamine uptake. In the case of NET and SERT one Na and one Cl ion are transported into the cell with one NE or 5-HT respectively. In the case of DAT two Na and one Cl ion are transported along with one DA. When ionic gradients are altered (extracellular K increases or extracellular Na or Cl decreases) transporters can function in reverse resulting in

6160-501: The use of SSRIs in the treatment of anorexia nervosa . Treatment guidelines from the National Institute of Health and Clinical Excellence recommend against the use of SSRIs in this disorder. Those from the American Psychiatric Association note that SSRIs confer no advantage regarding weight gain, but that they may be used for the treatment of co-existing depression, anxiety, or OCD. SSRIs have been used off-label in

6240-592: The use of SSRIs. A number of non-SSRI drugs are not associated with sexual side effects (such as bupropion , mirtazapine , tianeptine , agomelatine , tranylcypromine , and moclobemide ). Several studies have suggested that SSRIs may adversely affect semen quality. While trazodone (an antidepressant with alpha adrenergic receptor blockade) is a notorious cause of priapism , cases of priapism have also been reported with certain SSRIs (e.g. fluoxetine, citalopram). Post-SSRI sexual dysfunction (PSSD) refers to

6320-675: The world. The efficacy of SSRIs in mild or moderate cases of depression has been disputed and may or may not be outweighed by side effects, especially in adolescent populations. The main indication for SSRIs is major depressive disorder ; however, they are frequently prescribed for anxiety disorders , such as social anxiety disorder , generalized anxiety disorder , panic disorder , obsessive–compulsive disorder (OCD), eating disorders , chronic pain , and, in some cases, for posttraumatic stress disorder (PTSD). They are also frequently used to treat depersonalization disorder , although with varying results. Antidepressants are recommended by

6400-529: Was demonstrated to be differentially expressed in juvenile or adult mice. This differential expression coincided with decreased SSRI efficacy, and an anti-depressant-like effect of the PMAT inhibitor Decynium-22 , suggesting a tentative mechanism for treatment-resistant depression in human adolescents and children. Parkinson's disease states may be affected by PMAT activity at the synapse, due to its higher affinity for dopamine. In seeking to treat Parkinson's through increasing synaptic dopamine concentrations, it

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