Selective serotonin reuptake inhibitor

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Selective_serotonin_reuptake_inhibitor

 

Selective serotonin reuptake inhibitor
Drug class
Serotonin, the neurotransmitter that is involved in the mechanism of action of 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 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. 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.

Medical uses

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.

Depression

Antidepressants are recommended by 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.

• Two meta-analyses published in 2008 (Kirsch) and 2010 (Fournier) found that in mild and moderate depression, the effect of SSRIs is small or none compared to placebo, while in very severe depression the effect of SSRIs is between "relatively small" and "substantial". The 2008 meta-analysis combined 35 clinical trials submitted to the Food and Drug Administration (FDA) before licensing of four newer antidepressants (including the SSRIs paroxetine and fluoxetine, the non-SSRI antidepressant nefazodone, and the serotonin and norepinephrine reuptake inhibitor (SNRI) venlafaxine). The authors attributed the relationship between severity and efficacy to a reduction of the placebo effect in severely depressed patients, rather than an increase in the effect of the medication. Some researchers have questioned the statistical basis of this study suggesting that it underestimates the effect size of antidepressants.
• A 2012 meta-analysis of fluoxetine and venlafaxine concluded that statistically and clinically significant treatment effects were observed for each drug relative to placebo irrespective of baseline depression severity; some of the authors however disclosed substantial relationships with pharmaceutical industries.
• A 2017 systematic review stated that "SSRIs versus placebo seem to have statistically significant effects on depressive symptoms, but the clinical significance of these effects seems questionable and all trials were at high risk of bias. Furthermore, SSRIs versus placebo significantly increase the risk of both serious and non-serious adverse events. Our results show that the harmful effects of SSRIs versus placebo for major depressive disorder seem to outweigh any potentially small beneficial effects". Fredrik Hieronymus et al. criticized the review as inaccurate and misleading, but they also disclosed multiple ties to pharmaceutical industries and receipt of speaker's fees.
• In 2018, a systematic review and network meta-analysis comparing the efficacy and acceptability of 21 antidepressant drugs showed escitalopram to be one of the most effective. They showed that "In terms of efficacy, all antidepressants were more effective than placebo, with odds ratios (ORs) ranging between 2.13 (95% credible interval [CrI] 1.89–2.41) for amitriptyline and 1.37 (1.16–1.63) for reboxetine."

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 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.

Social anxiety disorder

Some SSRIs are effective for social anxiety disorder, although their effects on symptoms 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, too, escitalopram and citalopram are used off label with acceptable efficacy, while fluoxetine is not considered to be effective for this disorder.

Post-traumatic stress disorder

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 is used off label, but with mixed results; venlafaxine, an SNRI, is considered somewhat effective, although used off label, too. 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.

Generalized anxiety disorder

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 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 is similar.

Obsessive–compulsive disorder

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 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.

Panic disorder

Paroxetine CR was superior to placebo on the primary outcome measure. In a 10-wk 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.

Eating disorders

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 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 depressive, anxiety, or OCD.

Stroke recovery

SSRIs have been used off-label in the treatment of stroke patients, including those with and without symptoms of depression. A 2019 meta-analysis of randomized, controlled clinical trials found a statistically significant effect of SSRIs on dependence, neurological deficit, depression, and anxiety but the studies had a high risk of bias. No reliable evidence points to their routine use to promote recovery following stroke. Thrombosis risk is reduced because SSRIs limit serotonin availability to platelets, so benefits, such as stroke recovery, of reduced clotting go up, with SSRIs.

Premature ejaculation

Main article: Premature ejaculation

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 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 the desired effect.

Other uses

SSRIs such as sertraline have been found to be effective in decreasing anger.

Side effects

Side effects vary among the individual drugs of this class and may include:

• increased risk of bone fractures
• akathisia
• suicidal ideation (thoughts of suicide) and other risks (see below)

Sexual dysfunction

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. While initial trials showed side effects in 5–15% of users (based on spontaneous reporting by users), later studies (based on asking patients directly) have shown side effect rates from 36% to 98%. Poor sexual function is also one of the most common reasons people stop the medication.

In some cases, symptoms of sexual dysfunction may persist after discontinuation of SSRIs. This combination of symptoms is sometimes referred to as post-SSRI sexual dysfunction (PSSD). On the 11th of June 2019 the Pharmacovigilance Risk Assessment Committee of the European Medicines Agency concluded that a possible relationship exists between SSRI use and persistent sexual dysfunction after cessation of use. The committee concluded that a warning should be added to the label of SSRIs and SNRIs regarding this possible risk.

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 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.

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).

Emotional blunting

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 the medication, or switching to a different antidepressant that may have less propensity for causing this side effect.

Vision

Acute narrow-angle glaucoma is the most common and important ocular side effect of SSRIs, and often goes misdiagnosed.

Cardiac

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 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.

Bleeding

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 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.

Fracture risk

Evidence from longitudinal, cross-sectional, and prospective cohort studies suggests an association between SSRI usage at therapeutic doses and 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 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.

Bruxism

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

Main article: Serotonin syndrome

Serotonin syndrome 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 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 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.

Suicide risk

Children and adolescents

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, 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 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 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 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), and only for the treatment of obsessive–compulsive disorder. Fluoxetine is not licensed for this use.

Adults

It is unclear whether SSRIs affect the risk of suicidal behavior in adults.

• A 2005 meta-analysis of drug company data found no evidence that SSRIs increased the risk of suicide; however, important protective or hazardous effects could not be excluded.
• A 2005 review observed that suicide attempts are increased in those who use SSRIs as compared to placebo and compared to therapeutic interventions other than tricyclic antidepressants. No difference risk of suicide attempts was detected between SSRIs versus tricyclic antidepressants.
• On the other hand, a 2006 review suggests that the widespread use of antidepressants in the new "SSRI-era" appears to have led to a highly significant decline in suicide rates in most countries with traditionally high baseline suicide rates. The decline is particularly striking for women who, compared with men, seek more help for depression. Recent clinical data on large samples in the US too have revealed a protective effect of antidepressant against suicide.
• A 2006 meta-analysis of random controlled trials suggests that SSRIs increase suicide ideation compared with placebo. However, the observational studies suggest that SSRIs did not increase suicide risk more than older antidepressants. The researchers stated that if SSRIs increase suicide risk in some patients, the number of additional deaths is very small because ecological studies have generally found that suicide mortality has declined (or at least not increased) as SSRI use has increased.
• An additional meta-analysis by the FDA in 2006 found an age-related effect of SSRI's. Among adults younger than 25 years, results indicated that there was a higher risk for suicidal behavior. For adults between 25 and 64, the effect appears neutral on suicidal behavior but possibly protective for suicidal behavior for adults between the ages of 25 and 64. For adults older than 64, SSRI's seem to reduce the risk of both suicidal behavior.
• In 2016 a study criticized the effects of the FDA Black Box suicide warning inclusion in the prescription. The authors discussed the suicide rates might increase also as a consequence of the warning.

Risk of death

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.

Pregnancy and breastfeeding

SSRI use in pregnancy has been associated with a variety of risks with varying degrees of proof of causation. As depression 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 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 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 the safety of SSRIs has determined that some SSRIs like Sertraline and Paroxetine are considered safe for breastfeeding.

Neonatal abstinence syndrome

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 is available to determine whether there are long-term effects.

Persistent pulmonary hypertension

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 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 the newborn". A review published in 2012 reached conclusions very similar to those of the 2014 study.

Neuropsychiatric effects in offspring

According to a 2015 review available data found that "some signal exists suggesting that antenatal exposure to SSRIs may increase the risk of ASDs (autism spectrum disorders)" even though a large cohort study published in 2013 and a cohort study using data from Finland's national register between the years 1996 and 2010 and published in 2016 found no significant association between SSRI use and autism in offspring. The 2016 Finland study also found no association with ADHD, but did find an association with increased rates of depression diagnoses in early adolescence.

Bipolar switch

In adults and children with bipolar disorder, SSRIs may cause a bipolar switch from depression into hypomania/mania. When taken with mood stabilizers, the risk of switching is not increased, however when taking SSRI's as a monotherapy, the risk of switching may be twice or three times that of the average. The changes are not often easy to detect and require monitoring by family and mental health professionals. This switch might happen even with no prior (hypo)manic episodes and might therefore not be foreseen by the psychiatrist.

Interactions

The following drugs may precipitate serotonin syndrome in people on SSRIs:

• Linezolid
• Monoamine oxidase inhibitors (MAOIs) including moclobemide, phenelzine, tranylcypromine, selegiline and methylene blue
• Lithium
• Sibutramine
• MDMA (ecstasy)
• Dextromethorphan
• Tramadol
• 5-HTP
• Pethidine/meperidine
• St. John's wort
• Yohimbe
• Tricyclic antidepressants (TCAs)
• Serotonin-norepinephrine reuptake inhibitors (SNRIs)
• Buspirone
• Triptan
• Mirtazapine
• Methylene blue

Painkillers of the NSAIDs drug family may interfere and reduce efficiency of SSRIs and may compound the increased risk of gastrointestinal bleeds caused by SSRI use. NSAIDs include:

• Aspirin
• Ibuprofen (Advil, Nurofen)
• Naproxen (Aleve)

There are a number of potential pharmacokinetic interactions between the various individual SSRIs and other medications. Most of these arise from the fact that every SSRI has the ability to inhibit certain P450 cytochromes.

Drug name	CYP1A2	CYP2C9	CYP2C19	CYP2D6	CYP3A4	CYP2B6
Citalopram	+	0	0	+	0	0
Escitalopram	0	0	0	+	0	0
Fluoxetine	+	++	+/++	+++	+	+
Fluvoxamine	+++	++	+++	+	+	+
Paroxetine	+	+	+	+++	+	+++
Sertraline	+	+	+/++	+	+	+

Legend:
0 – no inhibition
+ – mild inhibition
++ – moderate inhibition
+++ – strong inhibition

The CYP2D6 enzyme is entirely responsible for the metabolism of hydrocodone, codeine and dihydrocodeine to their active metabolites (hydromorphone, morphine, and dihydromorphine, respectively), which in turn undergo phase 2 glucuronidation. These opioids (and to a lesser extent oxycodone, tramadol, and methadone) have interaction potential with selective serotonin reuptake inhibitors. The concomitant use of some SSRIs (paroxetine and fluoxetine) with codeine may decrease the plasma concentration of active metabolite morphine, which may result in reduced analgesic efficacy.

Another important interaction of certain SSRIs involves paroxetine, a potent inhibitor of CYP2D6, and tamoxifen, an agent used commonly in the treatment and prevention of breast cancer. Tamoxifen is a prodrug that is metabolised by the hepatic cytochrome P450 enzyme system, especially CYP2D6, to its active metabolites. Concomitant use of paroxetine and tamoxifen in women with breast cancer is associated with a higher risk of death, as much as a 91 percent in women who used it the longest.

Overdose

See also: Serotonin syndrome

SSRIs appear safer in overdose when compared with traditional antidepressants, such as the tricyclic antidepressants. This relative safety is supported both by case series and studies of deaths per numbers of prescriptions. However, case reports of SSRI poisoning have indicated that severe toxicity can occur and deaths have been reported following massive single ingestions, although this is exceedingly uncommon when compared to the tricyclic antidepressants.

Because of the wide therapeutic index of the SSRIs, most patients will have mild or no symptoms following moderate overdoses. The most commonly reported severe effect following SSRI overdose is serotonin syndrome; serotonin toxicity is usually associated with very high overdoses or multiple drug ingestion. Other reported significant effects include coma, seizures, and cardiac toxicity.

Poisoning is also known in animals, and some toxicity information is available for veterinary treatment.

Discontinuation syndrome

Main article: SSRI discontinuation syndrome

Serotonin reuptake inhibitors should not be abruptly discontinued after extended therapy, and whenever possible, should be tapered over several weeks to minimize discontinuation-related symptoms which may include nausea, headache, dizziness, chills, body aches, paresthesias, insomnia, and brain zaps. Paroxetine may produce discontinuation-related symptoms at a greater rate than other SSRIs, though qualitatively similar effects have been reported for all SSRIs. Discontinuation effects appear to be less for fluoxetine, perhaps owing to its long half-life and the natural tapering effect associated with its slow clearance from the body. One strategy for minimizing SSRI discontinuation symptoms is to switch the patient to fluoxetine and then taper and discontinue the fluoxetine.

Mechanism of action

Serotonin reuptake inhibition

In the brain, messages are passed from a nerve cell to another via a chemical synapse, a small gap between the cells. The presynaptic cell that sends the information releases neurotransmitters including serotonin into that gap. The neurotransmitters are then recognized by receptors on the surface of the recipient postsynaptic cell, which upon this stimulation, in turn, relays the signal. About 10% of the neurotransmitters are lost in this process; the other 90% are released from the receptors and taken up again by monoamine transporters into the sending presynaptic cell, a process called reuptake.

SSRIs inhibit the reuptake of serotonin. As a result, the serotonin stays in the synaptic gap longer than it normally would, and may repeatedly stimulate the receptors of the recipient cell. In the short run, this leads to an increase in signaling across synapses in which serotonin serves as the primary neurotransmitter. On chronic dosing, the increased occupancy of post-synaptic serotonin receptors signals the pre-synaptic neuron to synthesize and release less serotonin. Serotonin levels within the synapse drop, then rise again, ultimately leading to downregulation of post-synaptic serotonin receptors. Other, indirect effects may include increased norepinephrine output, increased neuronal cyclic AMP levels, and increased levels of regulatory factors such as BDNF and CREB. Owing to the lack of a widely accepted comprehensive theory of the biology of mood disorders, there is no widely accepted theory of how these changes lead to the mood-elevating and anti-anxiety effects of SSRIs.

Their effects on serotonin blood levels, which take weeks to take effect, appear to be largely responsible for their slow-to-appear psychiatric effects. SSRIs mediate their action largely with high occupancy in a total of all serotonin transporters within the brain and through this slow downstream changes of large brain regions at therapeutic concentrations, whereas MDMA leads to an excess serotonin release in a short run. This could explain the absence of a "high" by antidepressants and in addition the contrary ability of SSRIs in expressing neuroprotective actions to the neurotoxic abilities of MDMA.

Sigma receptor ligands

SSRIs at the human SERT and rat sigma receptors

Medication	SERT	σ1		σ2	σ1 / SERT
Citalopram	1.16	292–404	Agonist	5,410	252–348
Escitalopram	2.5	288	Agonist	ND	ND
Fluoxetine	0.81	191–240	Agonist	16,100	296–365
Fluvoxamine	2.2	17–36	Agonist	8,439	7.7–16.4
Paroxetine	0.13	≥1,893	ND	22,870	≥14,562
Sertraline	0.29	32–57	Antagonist	5,297	110–197
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.

In addition to their actions as reuptake inhibitors of serotonin, some SSRIs are also, coincidentally, ligands of the sigma receptors. Fluvoxamine is an agonist of the σ₁ receptor, while sertraline is an antagonist of the σ₁ receptor, and paroxetine does not significantly interact with the σ₁ receptor. None of the SSRIs have significant affinity for the σ₂ receptor, and the SNRIs, unlike the SSRIs, do not interact with either of the sigma receptors. Fluvoxamine has by far the strongest activity of the SSRIs at the σ₁ receptor. High occupancy of the σ₁ receptor by clinical dosages of fluvoxamine has been observed in the human brain in positron emission tomography (PET) research. It is thought that agonism of the σ₁ receptor by fluvoxamine may have beneficial effects on cognition. In contrast to fluvoxamine, the relevance of the σ₁ receptor in the actions of the other SSRIs is uncertain and questionable due to their very low affinity for the receptor relative to the SERT.

Anti-inflammatory effects

The role of inflammation and the immune system in depression has been extensively studied. The evidence supporting this link has been shown in numerous studies over the past ten years. Nationwide studies and meta-analyses of smaller cohort studies have uncovered a correlation between pre-existing inflammatory conditions such as type 1 diabetes, rheumatoid arthritis (RA), or hepatitis, and an increased risk of depression. Data also shows that using pro-inflammatory agents in the treatment of diseases like melanoma can lead to depression. Several meta-analytical studies have found increased levels of proinflammatory cytokines and chemokines in depressed patients. This link has led scientists to investigate the effects of antidepressants on the immune system.

SSRIs were originally invented with the goal of increasing levels of available serotonin in the extracellular spaces. However, the delayed response between when patients first begin SSRI treatment to when they see effects has led scientists to believe that other molecules are involved in the efficacy of these drugs. To investigate the apparent anti-inflammatory effects of SSRIs, both Kohler et al. and Więdłocha et al. conducted meta-analyses which have shown that after antidepressant treatment the levels of cytokines associated with inflammation are decreased. A large cohort study conducted by researchers in the Netherlands investigated the association between depressive disorders, symptoms, and antidepressants with inflammation. The study showed decreased levels of interleukin (IL)-6, a cytokine that has proinflammatory effects, in patients taking SSRIs compared to non-medicated patients.

Treatment with SSRIs has shown reduced production of inflammatory cytokines such as IL-1β, tumor necrosis factor (TNF)-α, IL-6, and interferon (IFN)-γ, which leads to a decrease in inflammation levels and subsequently a decrease in the activation level of the immune response. These inflammatory cytokines have been shown to activate microglia which are specialized macrophages that reside in the brain. Macrophages are a subset of immune cells responsible for host defense in the innate immune system. Macrophages can release cytokines and other chemicals to cause an inflammatory response. Peripheral inflammation can induce an inflammatory response in microglia and can cause neuroinflammation. SSRIs inhibit proinflammatory cytokine production which leads to less activation of microglia and peripheral macrophages. SSRIs not only inhibit the production of these proinflammatory cytokines, they also have been shown to upregulate anti-inflammatory cytokines such as IL-10. Taken together, this reduces the overall inflammatory immune response.

In addition to affecting cytokine production, there is evidence that treatment with SSRIs has effects on the proliferation and viability of immune system cells involved in both innate and adaptive immunity. Evidence shows that SSRIs can inhibit proliferation in T-cells, which are important cells for adaptive immunity and can induce inflammation. SSRIs can also induce apoptosis, programmed cell death, in T-cells. The full mechanism of action for the anti-inflammatory effects of SSRIs is not fully known. However, there is evidence for various pathways to have a hand in the mechanism. One such possible mechanism is the increased levels of cyclic adenosine monophosphate (cAMP) as a result of interference with activation of protein kinase A (PKA), a cAMP dependent protein. Other possible pathways include interference with calcium ion channels, or inducing cell death pathways like MAPK and Notch signaling pathway.

The anti-inflammatory effects of SSRIs have prompted studies of the efficacy of SSRIs in the treatment of autoimmune diseases such as multiple sclerosis, RA, inflammatory bowel diseases, and septic shock. These studies have been performed in animal models but have shown consistent immune regulatory effects. Fluoxetine, an SSRI, has also shown efficacy in animal models of graft vs. host disease. SSRIs have also been used successfully as pain relievers in patients undergoing oncology treatment. The effectiveness of this has been hypothesized to be at least in part due to the anti-inflammatory effects of SSRIs.

Pharmacogenetics

Further information: Pharmacogenetics

Large bodies of research are devoted to using genetic markers to predict whether patients will respond to SSRIs or have side effects that will cause their discontinuation, although these tests are not yet ready for widespread clinical use.

Versus TCAs

SSRIs are described as 'selective' because they affect only the reuptake pumps responsible for serotonin, as opposed to earlier antidepressants, which affect other monoamine neurotransmitters as well, and as a result, SSRIs have fewer side effects.

There appears to be no significant difference in effectiveness between SSRIs and tricyclic antidepressants, which were the most commonly used class of antidepressants before the development of SSRIs. However, SSRIs have the important advantage that their toxic dose is high, and, therefore, they are much more difficult to use as a means to commit suicide. Further, they have fewer and milder side effects. Tricyclic antidepressants also have a higher risk of serious cardiovascular side effects, which SSRIs lack.

SSRIs act on signal pathways such as cyclic adenosine monophosphate (cAMP) on the postsynaptic neuronal cell, which leads to the release of brain-derived neurotrophic factor (BDNF). BDNF enhances the growth and survival of cortical neurons and synapses.

List of SSRIs

Marketed

Neurotransmitter transporters inhibitors

  Serotonin transporter inhibitors

Antidepressants

• Citalopram (Celexa)
• Escitalopram (Lexapro)
• Fluoxetine (Prozac)
• Fluvoxamine (Luvox)
• Paroxetine (Paxil)
• Sertraline (Zoloft)

Others

• Dapoxetine (Priligy)

Discontinued

Antidepressants

• Indalpine (Upstène)
• Zimelidine (Zelmid)

Never marketed

Antidepressants

• Alaproclate (GEA-654)
• Centpropazine
• Cericlamine (JO-1017)
• Femoxetine (Malexil; FG-4963)
• Ifoxetine (CGP-15210)
• Omiloxetine
• Panuramine (WY-26002)
• Pirandamine (AY-23713)
• Seproxetine ((S)-norfluoxetine)

Related drugs

Although described as SNRIs, duloxetine (Cymbalta), venlafaxine (Effexor), and desvenlafaxine (Pristiq) are in fact relatively selective as serotonin reuptake inhibitors (SRIs). They are about at least 10-fold selective for inhibition of serotonin reuptake over norepinephrine reuptake. The selectivity ratios are approximately 1:30 for venlafaxine, 1:10 for duloxetine, and 1:14 for desvenlafaxine. At low doses, these SNRIs act mostly as SSRIs; only at higher doses do they also prominently inhibit norepinephrine reuptake. Milnacipran (Ixel, Savella) and its stereoisomer levomilnacipran (Fetzima) are the only widely marketed SNRIs that inhibit serotonin and norepinephrine to similar degrees, both with ratios close to 1:1.

Vilazodone (Viibryd) and vortioxetine (Trintellix) are SRIs that also act as modulators of serotonin receptors and are described as serotonin modulators and stimulators (SMS). Vilazodone is a 5-HT_1A receptor partial agonist while vortioxetine is a 5-HT_1A receptor agonist and 5-HT₃ and 5-HT₇ receptor antagonist. Litoxetine (SL 81–0385) and lubazodone (YM-992, YM-35995) are similar drugs that were never marketed. They are SRIs and litoxetine is also a 5-HT₃ receptor antagonist while lubazodone is also a 5-HT_2A receptor antagonist.

History

See also: Development and discovery of SSRI drugs

Fluoxetine was introduced in 1987 and was the first major SSRI to be marketed.

Controversy

See also: Biopsychiatry controversy and Biological psychiatry

A study examining publication of results from FDA-evaluated antidepressants concluded that those with favorable results were much more likely to be published than those with negative results. Furthermore, an investigation of 185 meta-analyses on antidepressants found that 79% of them had authors affiliated in some way to pharmaceutical companies and that they were reluctant to report caveats for antidepressants.

David Healy has argued that warning signs were available for many years prior to regulatory authorities moving to put warnings on antidepressant labels that they might cause suicidal thoughts. At the time these warnings were added, others argued that the evidence for harm remained unpersuasive and others continued to do so after the warnings were added.

In other organisms

SSRIs are common environmental contaminant findings near human settlement.

Veterinary use

An SSRI (fluoxetine) has been approved for veterinary use in treatment of canine separation anxiety.

Anti-LGBT curriculum laws in the United States

From Wikipedia, the free encyclopedia
https://en.wikipedia.org/wiki/Anti-LGBT_curriculum_laws_in_the_United_States

Anti-LGBT curriculum laws, sometimes referred to as "Don't Say Gay" laws or no promo homo laws, are laws approved by various U.S. states that prohibit or limit the mention or discussion of homosexuality and transgender identity in public schools, especially in younger grades. In theory, these laws mainly apply to sex ed courses, but they can also be applied to other parts of the school curriculum as well as to extracurricular activities such as sports and organizations such as gay–straight alliances. In July 2022, a wave of anti-LGBT curriculum resurgence saw ten such laws beginning to take effect in six different states. Some states enacting these new laws appear to have mirrored similar laws from other states.

In Florida, the Parental Rights in Education law and Florida Board of Education policy bans education on "sexual orientation" or "gender identity" unless it is mandated under state academic standards or as part of an optional reproductive health course or lesson, while Alabama bans the topics from kindergarten to grade 5, except for instruction deemed "age or developmentally appropriate," and Iowa bans the topics from kindergarten to grade 6. Five other states (Montana, Arizona, Arkansas, Tennessee and Florida) require parental notification of instruction on LGBTQ issues and allows parents to opt-out of such instruction.

State laws

Texas

Texas Statute Books currently contain two Anti-LGBT curriculum laws:

"The materials in the education programs intended for persons younger than 18 years of age must: (1) emphasize sexual abstinence before marriage and fidelity in marriage as the expected standard." Tex. Health & Safety Code § 85.007.

"Course materials and instruction relating to sexual education or sexually transmitted diseases should include: [...] (8) emphasis, provided in a factual manner and from a public health perspective, that homosexuality is not a lifestyle acceptable to the general public." Tex. Health & Safety Code § 163.002.

In November 2020, the Texas Board of Education had an opportunity to update these laws, but the Republican majority voted not to in a 9-6 vote. Despite this, they did vote in favor of updating the anti-bullying policy to include language about "sexual bullying", although it was unclear if this included LGBT students or not, and when the Conservative board members were questioned what the term meant, they could not give a straight definition.

As of March 2022, the Texas Anti-LGBT curriculum laws remain on the Statute books.

Florida

Main article: Florida Parental Rights in Education Act

In March 2022, the Florida Legislature passed House Bill 1557, the Parental Rights in Education Act, often referred to as the "Don't Say Gay" bill by its opponents. Governor of Florida Ron DeSantis signed the bill into law on March 28, 2022. The law goes into effect from July 1. The law prohibits classroom instruction on sexual orientation or gender identity from kindergarten to grade 3 in Florida public school districts, or instruction on sexual orientation or gender identity in a manner that is not "age appropriate or developmentally appropriate for students" in any grade. The preamble of the law also mentions "classroom discussion" of these topics, dividing legal scholars if that would be included within the scope of the law. It also allows parents and teachers to sue any school district if they believe this policy is violated, with school districts covering the cost of the lawsuit. The bill additionally prevents school districts from withholding information about a child's "mental, emotional, or physical well-being" from their parents. Due to the "Don't Say Gay" nickname, some commentators and social media users incorrectly believed the bill banned mentioning the word "gay" in school classrooms. The bill does not verbatim prohibit the use of the word "gay;" it prohibits classroom instruction or "discussion" on "sexual orientation or gender identity."

The bill is currently being contested by a lawsuit in the United States District Court for the Northern District of Florida alleging intrusions on the First Amendment , violates Title IX, and Due Process. In October 2022, federal judge Wendy Berger dismissed the suit, for lack of standing, which challenged the legislation effective since July 1. She gave the plaintiffs 14 days to file a revised lawsuit.

In 2023, Ron Desantis called for the Florida Parental Rights in Education Act to be expanded to the twelfth grade, hence banning all discussion on gender and sexual orientation topics.

Alabama

In April 2021, Alabama governor Kay Ivey signed a repeal of a 1992 law that required "Course materials and instruction that relate to sexual education or sexually transmitted diseases should include ... an emphasis, in a factual manner and from a public health perspective, that homosexuality is not a lifestyle acceptable to the general public and that homosexual conduct is a criminal offense under the laws of the state." Ala. Code § 16-40A-2. However, in 2022, Ivey signed similar legislation prohibiting LGBT instruction in 2022 after Florida passed its law.

Repealed laws

Arizona

In April 2019, the Arizona State Legislature passed (House vote 55–5 and Senate vote 19–10) and the Governor of Arizona signed a repeal of the 1991 HIV law (ARS § 15-716) that prohibited AIDS and HIV-related "instruction which: 1. Promotes a homosexual life-style. 2. Portrays homosexuality as a positive alternative life-style. 3. Suggests that some methods of sex are safe methods of homosexual sex." Due to several court cases running, the constitutionality of the law was questioned. The repeal went into effect on July 1, 2019.

North Carolina

In 2006 with the passage of 2006 N.C. Sess. Laws 264,§ 54(a)–(c), the North Carolina State Legislature amended N.C. Gen. Stat. § 115C-81(e1)(3) to remove the prohibition of discussing homosexuality.

Utah

On October 21, 2016, Equality Utah filed a lawsuit with the U.S. District Court for the District of Utah against the Utah State Board of Education to strike down Utah Code § 53A-13-101(1)(c)(iii)(A). On March 8, 2017, the Utah State Legislature passed SB196, which removes the phrase "the advocacy of homosexuality" from the law. On March 20, 2017, Governor Gary Herbert signed SB196 into law. The repeal went into effect on July 1, 2017.

The repealed statute stated "[T]he materials adopted by a local school board ... shall be based upon recommendations of the school district's Curriculum Materials Review Committee that comply with state law and state board rules emphasizing abstinence before marriage and fidelity after marriage, and prohibiting instruction in the advocacy of homosexuality." Utah Code § 53A-13-101.

Overturned laws

South Carolina

On March 11, 2020, the US District Court of South Carolina ruled in GSA v. Spearman that South Carolina's anti-LGBT curriculum law "cannot satisfy any level of judicial review under the Equal Protection Clause". The Court ordered that "[t]he Superintendent and the Superintendent's officers, assigns, successors, agents, employees, attorneys, and other persons who are acting in concert or in participation with each or any of them, are permanently enjoined from enforcing, applying, or relying on S.C. Code. § 59-32-30(A)(5)." This rendered S.C. Code. § 59-32-30(A)(5) unenforceable.

The judgement was a consent decree. The defendant, the superintendent of the South Carolina Department of Education, agreed that the law was likely unconstitutional after receiving advice from South Carolina Attorney General Alan Wilson and decided to accept the Court's terms.

Proposed laws

Federal

Main article: Stop the Sexualization of Children Act

In October 2022, 32 Republicans co-sponsored Louisiana representative Mike Johnson's Stop the Sexualization of Children Act, modeled after the 2022 Florida Parental Rights in Education Act, with it also earning the nickname of the "national Don't Say Gay law." It would use denial of federal funds to enforce similar rules.

Alabama

On April 7, 2022, an amendment to House Bill 322, which requires all multiple occupancy restrooms or changing areas designated for student use in public K-12 schools to be used by individuals based on their biological sex, was offered and passed in the Alabama Senate. On page 2, after line 27 of the original bill, it amends "An individual or group of individuals providing classroom instruction to students in kindergarten through the fifth grade at a public K-12 school shall not engage in classroom discussion or provide classroom instruction regarding sexual orientation or gender identity in a manner that is not age appropriate or developmentally appropriate for students in accordance with state standards." The bill was signed by Governor Kay Ivey in April 2022 and is scheduled to go into effect this summer.

Ohio

On April 4, 2022, House Bill 616 was introduced to the Ohio General Assembly by Mike Loychik and Jean Schmidt. Starting on page 3, line 51, it says "No school district, community school, STEM school, nonpublic school that enrolls students who are participating in a state scholarship program, or any employee or other third party representing a school district or school shall do either of the following: (a) With respect to a student in any of grades kindergarten through three, teach, use, or provide any curriculum or instructional materials on sexual orientation or gender identity; (b) With respect to a student in any of grades four through twelve, teach, use, or provide any curriculum or instructional materials on sexual orientation or gender identity in any manner that is not age-appropriate or developmentally appropriate for students in accordance with state standards. [...]"

South Carolina

On January 11, 2022 House Bill 4555, called the "Parental Bill of Rights", was introduced into the South Carolina General Assembly. If the proposed bill passes, the bill would require schools to provide "...procedures for a parent to withdraw his child from any portion of the school district's comprehensive health education program required pursuant to Chapter 32, Title 59 that relates to sex education or instruction in acquired immune deficiency syndrome education or any instruction regarding sexuality..."

North Carolina

On April 29, 2021 House Bill 755, called the Parental Bill of Rights", was introduced into the North Carolina General Assembly. If the proposed bill passes, the bill would prevent inclusion in the curriculum of instruction of children in grades kindergarten through third grade about sexual orientation or gender identity.

Pulsar planet

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Pulsar_planet 

 

Artist's concept of a pulsar with planets

 

Artist's concept of a disk around a neutron star

 

Artist's conception of a planet around a white dwarf-pulsar binary

Pulsar planets are planets that are found orbiting pulsars, or rapidly rotating neutron stars. The first such planets to be discovered were around a millisecond pulsar in 1992 and were the first extrasolar planets to be confirmed as discovered. Pulsars are extremely precise clocks and even small planets can create detectable variations in pulsar traits; the smallest known exoplanet is a pulsar planet.

They are extremely rare, with only half a dozen listed by the NASA Exoplanet Archive. Only special processes can give rise to planet-sized companions around pulsars, and many are thought to be exotic bodies such as planets made of diamond that were formed through the partial destruction of a companion star. The intense radiation and winds consisting of electrons-positrons would tend to strip atmospheres away from such planets, thus making them unlikely abodes for life.

Formation

It is thought that the formation of planets requires the existence of a protoplanetary disk with a "dead zone" where there is no turbulence. There, planetesimals can form and accumulate without falling into the star. Compared to young stars, neutron stars have a much higher luminosity and thus the formation of a dead zone is hindered by the ionization of the disk by the neutron star's radiation, which allows the magnetorotational instability to trigger turbulence and thus destroy the dead zone. Thus, a disk needs to have a large mass if it is to give rise to planets.

There are several processes that could give rise to planetary systems:

• "First generation" planets are planets that orbited the star before it went supernova and became a neutron star: Massive stars tend to lack planets, possibly due to the difficulty in detecting them around very bright stars but also because the radiation from such stars would destroy the protoplanetary disks. Planet within about 4 astronomical units distance from the star risk being engulfed and destroyed when it becomes a red giant/red supergiant. During the supernova, the system loses about half of its mass and unless the neutron star is ejected in the same direction as the planet was moving at the time of the supernova, the planets are likely to detach from the system. None of the known pulsar planet systems are likely to have formed in this process.
• "Second generation planets" from material that falls back on the neutron star after a supernova: The material could theoretically reach a mass comparable to that of a protoplanetary disk, but is likely to dissipate too fast to allow the formation of planets. There are no known examples of planets around young neutron stars.
• "Third generation planets": A companion star is destroyed through the interaction with a neutron star, forming a low-mass disk. Neutron stars can emit energetic radiation that heats the companion star, until it overflows its Roche lobe and is eventually destroyed. Another mechanism is the emission of gravitational waves, which shrink the orbit until the companion star (in these cases often a white dwarf) breaks up. In a third mechanism, the neutron star penetrates the envelope of a larger star, causing it to break up and form a disk around the neutron star. Disks formed in these processes are much more massive than these formed through fallback and thus persist for longer times, allowing the formation of planets. They also contain heavy elements that are essential building blocks for planets, and part of the disk will be accreted by the neutron star and spins it up in the process. Alternatively, a light white dwarf is destroyed by the interaction with a more massive one; the light white dwarf gives rise to a debris disk that generates a planet while the larger white dwarf becomes a neutron star.
• A companion star may be destroyed during the interaction with a neutron star but leave a planet-sized remnant, such a system is known as a "black widow".
• Finally, it is possible that planets from companion stars or rogue planets are captured by a neutron star, or that a neutron star merged with the original host star of the planets. The latter process would form a "common envelope" which eventually breaks down to form a disk from which planets can develop.

Implications

The formation scenarios have consequences for the planets' composition: A planet formed from supernova debris is likely rich in metals and radioactive isotopes and may contain large quantities of water; one formed through the break-up of a white dwarf would be carbon rich and consist of large amounts of diamond; an actual white dwarf fragment would be extremely dense. As of 2022, the most common type of neutron star planet is a "diamond planet", a very low mass white dwarf. Other objects around neutron stars could include asteroids, comets and planetoids. More speculative scenarios are planets consisting of strange matter, which could occur much more close to the neutron stars than ordinary matter planets, potentially emitting gravitational waves.

Planets can interact with the magnetic field of a neutron star to produce so-called "Alfvén wings", these are wing-shaped electrical currents around the planet which inject energy into the planet and could produce detectable radio emissions.

Observability

Pulsars are extremely precise clocks and pulsar timing is highly regular. It is thus possible to detect very small objects around pulsars, down to the size of large asteroids, from changes in the timing of the pulsar hosting them. The timing needs to be corrected for the effects of the motions of Earth and the Solar System, errors in the position estimates of the pulsar and of the travel times of the radiation across the interstellar medium. Pulsars spin and slow down over time in highly regular fashion; planets alter this pattern through their gravitational attraction on the pulsar, causing a Doppler shift in the pulses. The technique could in theory be also used to detect exomoons around pulsar planets. There are limitations to pulsar planet visibility, however; pulsar glitches and changes in the pulsation mode can mimick the existence of planets.

The first known extrasolar planets to be discovered (in 1992) were the pulsar planets around PSR B1257+12. The discovery demonstrated that exoplanets can be detected from Earth, and led to the expectation that extrasolar planets might not be uncommon. As of 2016 the least massive known extrasolar planet (only 0.02 M_Earth) is a pulsar planet.

However, the size and particular spectroscopic traits makes actually visualizing such planets very difficult. Pulsars are very small and thus the probability of a planet transiting in front of the pulsar - one potential way to image them - is very low. Spectroscopic analyses of planets are rendered difficult by the complicated spectra of pulsars. Interactions between a planetary magnetic field and the pulsar and the thermal emissions of planets are more likely avenues of getting information on the planets.

Occurrence

As of 2022 only half a dozen pulsar planets are known, implying an occurrence rate of no more than one planetary system per 200 neutron stars. Most of the planet formation scenarios require that the precursor be a binary star with one star much more massive than the other, and that the system survives the supernova that generated the pulsar. Both these conditions are rarely met and thus the formation of pulsar planets is a rare process. Additionally, planets and their orbits would have to survive the energetic radiation emitted by pulsars, including X-rays, gamma rays and energetic particles ("pulsar wind"). This would be particularly important for millisecond pulsars that were spun up by accretion, while they formed X-ray binaries; the radiation emitted under these circumstances would evaporate any planet. Pulsars remain visible for only a few million years, less than the time it takes for a planet to form, thus limiting the chance of observing one.

Based on the known occurrence rate of pulsar planets, there might be as many as 10 millions of them in the Milky Way. All known pulsar planets are found around millisecond pulsars, these are old pulsars that were spun up through the accrual of mass from a companion. As of 2015 there are no known planets around young pulsars; they are less regular than millisecond pulsars and thus detecting planets is more difficult.

Examples

Among the better known pulsar planets are:

• The pulsar PSR B1257+12, 1300 lightyears away in the constellation Virgo, was confirmed to have planets in 1992 based on observations made with the Arecibo Observatory. The system consists of one tiny planet with a mass of 0.02±0.002 Earth masses and two Super-Earths with masses 4.3±0.2 and 3.9±0.2 times that of Earth, assuming that the pulsar has a mass of 1.4 solar masses. They most likely formed from a protoplanetary disk, probably generated from the destruction of a companion star. Computer simulations have shown that the system should be stable for at least one billion years and that exomoons could survive in the system. The system resembles the inner Solar System; the planets orbit the pulsar at distances comparable to that of Mercury to the Sun and may have comparable surface temperatures. Reports of additional bodies in this system might be due to solar disturbances.
• A cthonian planet with a mass comparable to Jupiter but less than 40% of its radius orbits the pulsar PSR J1719-1438. This planet is probably the remnant of a companion star that was evaporated by the pulsar's radiation and has been described as a "diamond planet".
• A circumbinary planet with a mass of 2.5±1 Jupiter masses orbits around PSR B1620-26, a binary star consisting of a pulsar and a white dwarf in the globular cluster M4. This planet may have been captured into the pulsar's orbit, a process which is particularly likely within the packed environment of a globular cluster, and may be about 12.6 billion years old, making it the oldest known planet. Its existence may demonstrate that planets can form in low-metallicity globular clusters.
• PSR J2322-2650 seems to have a roughly Jupiter-mass companion. The radiation from the pulsar could be heating it to temperatures of about 2,300 K (2,030 °C); an light source observed close to the pulsar may be the planet. This pulsar is considerably less luminous than many, which may explain why the planet has survived to this day.

The parameters of known pulsar planetary system

Companion (in order from star)	Mass	Semimajor axis (AU)	Orbital period (days)	Eccentricity	Inclination	Radius
PSR B0329+54b	1.97±0.19 M🜨	10.26±0.07	10140±11	0.236±0.011	—	—
PSR B1257+12b	0.02±0.002 M🜨	0.19	25.262±0.003	0	—	—
PSR B1257+12c	4.3±0.2 M🜨	0.36	66.5419±0.0001	0.0186±0.0002	—	—
PSR B1257+12d	3.9±0.2 M🜨	0.46	98.2114±0.0002	—	—	—
PSR B1620-26b	2.5±1.0 MJ	23	—	—	—	—
PSR J1719-1438b	>1.2 MJ	—	0.090706293±0.000000002	<0.06	—	—
PSR J2322-2650b	0.7949±0.0002 MJ	—	0.322963997±0.000000006	<0.0017	—	—

Debris disks and precursors

Timing variations of the pulsars PSR J1937+21 and PSR J0738-4042 may reflect the existence of an asteroid belt around the pulsars, and collisions between asteroids/comets and neutron stars have been proposed as an explanation for the phenomenon of fast radio bursts, the gamma ray burst GRB 101225A and other types of pulsar variability. There are no known debris disks around pulsars, although the magnetars 4U 0142+61 and 1E 2259+586 have been suggested to harbour them.

The white dwarf-pulsar binary PSR J0348+0432 may be a system that could develop pulsar planets in the future. The existence of a dust cloud at the pulsar Geminga that may be a precursor to planets has been proposed.

Discredited candidates

There were earlier reports of pulsar planets which were either retracted or considered unconvincing, such as the 1991 "discovery" of a planet around PSR B1829-10 which turned out to be an artifact caused by the motion of the Earth. The existence of planets around the pulsar PSR B0329+54 has been debated since 1979 and is still unresolved as of 2017. PSR B1828-11 has been conclusively established to display magnetospheric activity that mimicks planets, without having any, and a planet candidate around the pulsar Geminga was later attributed to timing noise.

Habitability

See also: Habitability of neutron star systems

Pulsars emit a very different radiation than regular stars, with very little optical or infrared radiation but plenty of ionizing radiation and electron-positron pairs that are generated by the pulsar's magnetic field as it spins. Additionally, remnant heat from before the neutron star's birth, heating of the pulsar's poles from its own radiation and from mass accretion processes drives the emission of thermal radiation and neutrinos. The electron-positron pairs and X-rays are absorbed by planetary atmospheres and heat them, driving intense atmospheric escape that can strip them away. The presence of a planetary magnetic field could mitigate the impact of the electron-positron pairs.

Habitability is conventionally defined by the equilibrium temperature of a planet, which is a function of the amount of incoming radiation; a planet is defined "habitable" if liquid water can exist on its surface although even planets with little external energy can harbour underground life. Neutron stars do not emit large quantities of radiation given their small size; the habitable zone can easily end up lying so close to the star that tidal effects destroy the planets. Additionally, it is often unclear how much radiation a given neutron star emits and how much of it can actually reach a hypothetical planet's surface; of the known pulsar planets, only these of PSR B1257+12 are close to the habitable zone and as of 2015, no known pulsar planet is likely to be habitable. Additional heat sources may be radioactive isotopes such as potassium-40 formed during the supernova that gave rise to the pulsar and tidal heating for planets with close orbits. Radiation from outside sources such as companion stars would also add to the energy budget.

Landrace

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Landrace

 

Aerial roots of a maize landrace grown in nitrogen-depleted soils in the Sierra Mixe. Known for extensive aerial roots with a bacterial gel supplying 29%–82% of the plant's nitrogen supply.

A landrace is a domesticated, locally adapted, often traditional variety of a species of animal or plant that has developed over time, through adaptation to its natural and cultural environment of agriculture and pastoralism, and due to isolation from other populations of the species. Landraces are distinct from cultivars and from standard breeds.

A significant proportion of farmers around the world grow landrace crops, and most plant landraces are associated with traditional agricultural systems. Landraces of many crops have probably been grown for millennia. Increasing reliance upon modern plant cultivars that are bred to be uniform has led to a reduction in biodiversity, because most of the genetic diversity of domesticated plant species lies in landraces and other traditionally used varieties. Some farmers using scientifically improved varieties also continue to raise landraces for agronomic reasons that include better adaptation to the local environment, lower fertilizer requirements, lower cost, and better disease resistance. Cultural and market preferences for landraces include culinary uses and product attributes such as texture, color, or ease of use.

Domestic shorthair cat, a landrace of Felis catus

Plant landraces have been the subject of more academic research, and the majority of academic literature about landraces is focused on botany in agriculture, not animal husbandry. Animal landraces are distinct from ancestral wild species of modern animal stock, and are also distinct from separate species or subspecies derived from the same ancestor as modern domestic stock. Not all landraces derive from wild or ancient animal stock; in some cases, notably dogs and horses, domestic animals have escaped in sufficient numbers in an area to breed feral populations that form new landraces through evolutionary pressure.

Characteristics

There are differences between authoritative sources on the specific criteria which describe landraces, although there is broad consensus about the existence and utility of the classification. Individual criteria may be weighted differently depending on a given source's focus (e.g., governmental regulation, biological sciences, agribusiness, anthropology and culture, environmental conservation, pet -keeping and -breeding, etc.). Additionally, not all cultivars agreed to be landraces exhibit every characteristic of a landrace. General features that characterize a landrace may include:

A basket of landrace snap melons Cucumis melo subspecies agrestis, cultivar group Momordica from Pemba town, northern Mozambique. The landrace incorporates different colours and patterns of the fruit surface and is the only melon cultivar group in northern Mozambique.

• It is morphologically distinctive and identifiable (i.e., has particular and recognizable characteristics or properties), yet remains "dynamic".
• It is genetically adapted to, and has a reputation for being able to withstand, the conditions of the local environment, including climate, disease and pests, even cultural practices.
• It is not the product of formal (governmental, organizational, or private) breeding programs, and may lack systematic selection, development and improvement by breeders.
• It is maintained and fostered less deliberately than a standardized breed, with its genetic isolation principally a matter of geography acting upon whatever animals that happened to be brought by humans to a given area.
• It has a historical origin in a specific geographic area, will usually have its own local name(s), and will often be classified according to intended purpose.
• Where yield (e.g. of a grain or fruit crop) can be measured, a landrace will show high stability of yield, even under adverse conditions, but a moderate yield level, even under carefully managed conditions.
• At the level of genetic testing, its heredity will show a degree of integrity, but still some genetic heterogeneity (i.e. genetic diversity).

Terminology

See also: Breed, Cultivar, and Ecotype

Landrace literally means 'country-breed' (German: Landrasse) and close cognates of it are found in various Germanic languages. The first known reference to the role of landraces as genetic resources was made in 1890 at an agriculture and forestry congress in Vienna, Austria. The term was first defined by Kurt von Rümker in 1908, and more clearly described in 1909 by U. J. Mansholt, who wrote that landraces have more stable characteristics and better resistance to adverse conditions, but have lower production capacity than cultivars, and are apt to change genetically when moved to another environment. H. Kiessling added in 1912 that a landrace is a mixture of phenotypic forms despite relative outward uniformity, and a great adaptability to its natural and human environment.

The word landrace entered non-academic English in the early 1930s, by way of the Danish Landrace pig, a particular breed of lop-eared swine. Many other languages do not use separate terms, like landrace and breed, but instead rely on extended description to convey such distinctions. Spanish is one such language.

Geneticist D. Phillip Sponenberg described animal breeds within these classes: the landrace, the standardized breed, modern "type" breeds, industrial strains, and feral populations. He describes landraces as an early stage of breed development, created by a combination of founder effect, isolation, and environmental pressures. Human selection for production goals is also typical of landraces.

As discussed in more detail in breed, that term itself has several definitions from various scientific and animal husbandry perspectives. Some of those senses of breed relate to the concept of landraces. A Food and Agriculture Organization of the United Nations (FAO) guideline defines landrace and landrace breed as "a breed that has largely developed through adaptation to the natural environment and traditional production system in which it has been raised." This is in contrast to its definition of standardized breed: "a breed of livestock that was developed according to a strict programme of genetic isolation and formal artificial selection to achieve a particular phenotype."

In various domestic species (including pigs, goats, sheep and geese) some standardized breeds include "Landrace" in their names, but do not meet widely used definitions of landraces. For example, the British Landrace pig is a standardized breed, derived from earlier breeds with "Landrace" names.

Farmers' variety, usually applied to local cultivars, or seen as intermediate between a landrace and a cultivar, may also include landraces when referring to plant varieties not subjected to formal breeding programs.

Autochthonous and allochthonous landraces

A landrace native to, or produced for a long time within the agricultural system in which it is found is referred to as an autochthonous landrace, while a more recently introduced one is termed an allochthonous landrace.

Within academic agronomy, the term autochthonous landrace is sometimes used with a more technical, productivity-related definition, synthesized by A. C. Zeven from previous definitions beginning with Mansholt's: "an autochthonous landrace is a variety with a high capacity to tolerate biotic and abiotic stress, resulting in a high yield stability and an intermediate yield level under a low input agricultural system."

The terms autochthonous and allochthonous are most often applied to plants, with animals more often being referred to as indigenous or native. Examples of references in sources to long-term local landraces of livestock include constructions such as "indigenous landraces of sheep", and "Leicester Longwool sheep were bred to the native landraces of the region". Some usage of autochthonous does occur in reference to livestock, e.g. "autochthonous races of cattle such as the Asturian mountain cattle – Ratina and Casina – and Tudanca cattle."

Biodiversity and conservation

A morphologically diverse group of fruit from the Zapallo Plomo landrace of Cucurbita maxima squash

A significant proportion of farmers around the world grow landrace crops. However, as industrialized agriculture spreads, cultivars, which are selectively bred for high yield, rapid growth, disease and drought resistance, and other commercial production values, are supplanting landraces, putting more and more of them at risk of extinction.

In 1927 at the International Agricultural Congress, organized by the predecessor of the FAO, an extensive discussion was held on the need to conserve landraces. A recommendation that members organize nation-by-nation landrace conservation did not succeed in leading to widespread conservation efforts.

Landraces are often free from many intellectual property and other regulatory encumbrances. However, in some jurisdictions, a focus on their production may result in missing out on some benefits afforded to producers of genetically selected and homogenous organisms, including breeders' rights legislation, easier availability of loans and other business services, even the right to share seed or stock with others, depending on how favorable the laws in the area are to high-yield agribusiness interests.

As Regine Andersen of the Fridtjof Nansen Institute (Norway) and the Farmers' Rights Project puts it, "Agricultural biodiversity is being eroded. This trend is putting at risk the ability of future generations to feed themselves. In order to reverse the trend, new policies must be implemented worldwide. The irony of the matter is that the poorest farmers are the stewards of genetic diversity." Protecting farmer interests and protecting biodiversity is at the heart of the International Treaty on Plant Genetic Resources for Food and Agriculture (the "Plant Treaty" for short), under the Food and Agriculture Organization of the United Nations (FAO), though its concerns are not exclusively limited to landraces.

Landraces played a basic role in the development of the standardized breeds but are today threatened by the market success of the standardized breeds. In developing countries, landraces still play an important role, especially in traditional production systems. Specimens within an animal landrace tend to be genetically similar, though more diverse than members of a standardized or formal breed.

Carosello and Barattiere, Italian landraces of Cucumis melo whose fruits are eaten unripe

In situ and ex situ landrace conservation

Two approaches have been used to conserve plant landraces:

• in situ where the landrace is grown and conserved by farmers on farms.
• ex situ where the landrace is conserved in an artificial environment such as a gene-bank, using controls such as laminated packets kept frozen at −18 °C (0 °F).

As the amount of agricultural land dedicated to growing landrace crops declines, such as in the example of wheat landraces in the Fertile Crescent, landraces can become extinct in cultivation. Therefore ex situ landrace conservation practices are considered a way to avoid losing the genetic diversity completely. Research published in 2020 suggested that existing ways of cataloging diversity within ex situ genebanks fall short of cataloging the appropriate information for landrace crops.

An in situ conservation effort to save the Berrettina di Lungavilla squash landrace made use of participatory plant breeding practices in order to incorporate the local community into the work.

Preserving cereal landraces

Preservation efforts for cereal strains are ongoing including in situ and in online-searchable germplasm collections (seed banks), coordinated by Biodiversity International and the National Institute of Agricultural Botany (NIAB, UK). However, more may need to be done, because plant genetic variety, the source of crop health and seed quality, depends on a diversity of landraces and other traditionally used varieties. Efforts (as of 2008) were mostly focused on Iberia, the Balkans, and European Russia, and dominated by species from mountainous areas. Despite their incompleteness, these efforts have been described as "crucial in preventing the extinction of many of these local ecotypes".

An agricultural study published in 2008 showed that landrace cereal crops began to decline in Europe in the 19th century such that cereal landraces "have largely fallen out of use" in Europe. Landrace cultivation in central and northwest Europe was almost eradicated by the early 20th century, due to economic pressure to grow improved, modern cultivars. While many in the region are already extinct, some have survived by being passed from generation to generation, and have also been revived by enthusiasts outside Europe to preserve European agriculture and food culture elsewhere. These survivals are usually for specific uses, such as thatch, and traditional European cuisine and craft beer brewing.

Plants

Plant landrace development

See also: Plant breeding § Evolutionary plant breeding

The label landrace includes regional cultigens that are genetically heterogeneous, but with enough characteristics in common to permit their recognition as a group. These characteristics are used by farmers to manage diversity and purity within landraces.

In some cultures, development of new landraces is typically limited to members of specific social groups, such as women or shaman. Maintaining existing landraces, like developing new landraces, requires that farmers be able to identify crop-specific characteristics and that those characteristics are passed on to following generations.

Over time, the process of identifying the distinguishing characteristic or characteristics of a new landrace is reinforced by cultivation processes; for example, descendants of a plant that is notably drought tolerant may become iteratively more so through selective breeding as farmers regard it as better for dry areas and prioritize planting it in those locations. This is one way in which farming systems can develop a portfolio of landraces over time that have specific ecological niches and uses.

Conversely, modern cultivars can also be developed into a landrace over time when farmers save seed and practice selective breeding.

Although landraces are often discussed once they have become endemic to a particular geographical region, landraces have always been moved over long and short distances. Some landraces can adapt to various environments, while others only thrive within specific conditions. Self-fertilizing and vegetatively populated species adapt by changing the frequencies of phenotypes. Outbreeding crops absorb new genotypes through intentional and unintentional hybridization, or through mutation.

Cultivars developed from landraces

Members of a landrace variety, selected for uniformity with regards to a unique feature over a period of time, can be developed into a farmers' variety or cultivar. Traits from landraces are valuable for incorporation into elite lines. Crop disease resistance genes from landraces can provide eternally-needed resistances to more widely-used, modern varieties.