Selective serotonin reuptake inhibitor
Encyclopedia
Selective serotonin re-uptake inhibitors or serotonin-specific reuptake inhibitor (SSRIs) are a class of compounds typically used as antidepressant
s in the treatment of depression, anxiety disorder
s, and some personality disorder
s. The efficacy of SSRIs is disputed. A 2010 meta-analysis
states that "The magnitude of benefit of antidepressant medication compared with placebo ... may be minimal or nonexistent, on average, in patients with mild or moderate symptoms. For patients with very severe depression, the benefit of medications over placebo is substantial." This analysis discarded a great majority of FDA-approved antidepressant studies, including those that used placebo washout periods typically used as controls.
SSRIs are believed to increase the extracellular
level of the neurotransmitter
serotonin
by inhibiting
its reuptake
into the presynaptic cell, increasing the level of serotonin
in the synaptic cleft available to bind to the postsynaptic receptor. They have varying degrees of selectivity for the other monoamine transporter
s, with pure SSRIs having only weak affinity for the noradrenaline
and dopamine transporter
.
SSRIs are the first class of psychotropic drugs discovered using the process called rational drug design, a process that starts with a specific biological target and then creates a molecule designed to affect it. They are the most widely prescribed antidepressants in many countries.
. SSRIs are frequently prescribed for anxiety disorder
s, such as social anxiety
, panic disorder
s, obsessive–compulsive disorder (OCD), eating disorder
s, chronic pain
and occasionally, for posttraumatic stress disorder (PTSD). They are also frequently used to treat depersonalization disorder
, although generally with poor results . Though not specifically indicated by the manufacturers, they are sometimes prescribed to treat irritable bowel syndrome
(IBS), Lichen simplex chronicus
and premature ejaculation
.
All SSRIs are approved in the U.S. for use with psychiatric disorders as outlined in the Diagnostic and Statistical Manual of Mental Disorders
(DSM IV).
Approved uses for SSRIs vary by country and are determined by the overseeing branch of government in charge of regulating drugs. In the U.S., the Food and Drug Administration (FDA) approves drugs after trial results have been submitted by the pharmaceutical companies. In Europe, drugs can be approved either by the European Medicines Agency
for human consumption throughout the European Union
or by the regulatory agencies of individual countries for use within those countries.. In Canada, the drug approval process is carried out by Health Canada
.
A general disadvantage of SSRIs in treating premature ejaculation is that they require continuous daily treatment to delay ejaculation significantly. For the occasional "on-demand" treatment, a few hours before coitus, clomipramine
gave better results than paroxetine in one study, while in another study both sertraline and clomipramine were indistinguishable from the pause–squeeze technique and inferior to paroxetine. The most recent research, conducted in 2007, suggests that on-demand treatment with sildenafil
(Viagra) offers a dramatic improvement in ejaculation delay and sexual satisfaction as compared with daily paroxetine, with on-demand sertraline, paroxetine or clomipramine, and with the pause–squeeze technique.
A widely-reported 2008 meta-analysis combined 35 clinical trials submitted to the U.S. Food and Drug Administration (FDA) before licensing of four newer antidepressants (including the SSRIs paroxetine
and fluoxetine
, and two non-SSRI antidepressants nefazodone
and venlafaxine
). The authors found that although the effect of antidepressants vs placebo
s was statistically significant
, it did not exceed the NICE
criteria for a clinically significant effect. In particular they found that the effect size
was very small for moderate depression but increased with severity reaching 'clinical significance' for very severe depression. The relationship between severity and efficacy was attributed 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 but even when they re-analyse the data they find that this is still below the NICE threshold for 'clinical significance' when all results are combined (although individually paroxetine and venflafaxine exceed this threshold).
A 2010 meta-analysis reached similar conclusions: in mild and moderate depression, specifically that the effect of SSRI is very small or none compared to placebo, while it is clinically significant in very severe depression.
s, serotonin-norepinephrine-dopamine reuptake inhibitors and selective serotonin reuptake enhancer
s are also serotonergic
antidepressants.
Many side effects disappear after the adaptation phase, when the antidepressant effects begin to come to prominence. However, despite being called general, the side effects and their durations are highly individual and drug-specific. Usually the treatment is begun with a small dose to see how the patient's body reacts to the drug, after that either the dose can be adjusted (e.g. Prozac in the UK is begun at a 20 mg dose, and then adjusted as necessary to 40 mg or 60 mg). Should the drug prove ineffective, or the side effects intolerable to the patient, another common route is to switch treatment to either another SSRI, or an SNRI
.
Mania
or hypomania
is a possible side effect. Users with some type of bipolar disorder
are at a much higher risk, however SSRI-induced mania in patients previously diagnosed with unipolar depression can trigger a bipolar diagnosis.
such as anorgasmia
, erectile dysfunction
, and diminished libido
. Initial studies found sexual side effects not significantly different from placebo, but since these studies relied on unprompted reporting, the frequency was probably underestimated. In more recent studies, doctors have specifically asked about sexual difficulties, and found that they are present in between 17% and 41% of patients, although the lack of placebo control in these studies means they are likely overestimates.
Stimulation of postsynaptic 5-HT2 and 5-HT3 receptors decreases dopamine
and norepinephrine release from the substantia nigra
. A number of drugs are not associated with sexual side effects (such as bupropion
, mirtazapine
and maprotiline
, some of which are also not associated with weight gain). As a result, sexual dysfunction caused by SSRIs can sometimes be mitigated by several different drugs. These include:
On the other hand, the effect of SSRIs to slow down sexual stimulation may be used as treatment; SSRIs have been proposed as a drug to treat premature ejaculation
.
of less than 0.0003 percent. SSRIs inhibit cardiac and vascular sodium, calcium
and potassium channel
s and prolong QT interval
s. However, a number of large studies of patients without known pre-existing heart disease have reported no EKG
changes related to SSRI use. In overdose, fluoxetine has been reported to cause sinus tachycardia
, myocardial infarction
, junctional rhythm
s and trigeminy. Some authors have suggested electrocardiographic
monitoring in patients with severe pre-existing cardiovascular disease who are taking SSRI's.
s such as SSRIs have some dependence
producing effects, most notably a withdrawal syndrome
. Their dependence producing properties (depending on the antidepressant) may not be as significant as other psychotropic drugs such as benzodiazepine
s; however, withdrawal symptoms nonetheless may be quite severe and even debilitating. SSRIs have little abuse
potential, but discontinuation can produce disturbing withdrawal symptoms that may be indistinguishable from a reoccurrence of the original illness. Since physical dependence
is a reality, discontinuation should be discussed with a medical practitioner before beginning treatment with this class of drugs.
When discontinuing an SSRI or SNRI some doctors may switch the patient to fluoxetine
due to its much longer half-life
. This may avoid many of the severe withdrawal symptoms associated with SSRI/SNRI discontinuation. This can be done either by administering a single 20 mg dose of fluoxetine
or by beginning on a low dosage of fluoxetine
and slowly tapering down. Any SSRI or SNRI may be requested in liquid form, which allows very gradual tapering. Alternatively, a patient wishing to stop taking an SSRI/SNRI may visit a compounding pharmacy where his or her prescription may be re-arranged into progressively smaller dosages. For example the lowest dose of cymbalta that can normally be prescribed is 20 mg in gel capsules; a compounding pharmacist may divide this into doses of 20, 15, 10, 5 and 2.5 mg so that a proper tapered reduction may take place.
caused directly by the previous use of SSRI antidepressant
s.
While apparently uncommon, it can last for months, years, or sometimes indefinitely after the discontinuation of SSRIs.
One or more of the following sexual
symptoms may persist or begin after the discontinuation of SSRIs:
s 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%.
More infrequently, studies have been inconclusive. There is also evidence that higher rates of SSRI prescriptions are associated with lower rates of suicide in children, though since the evidence is correlation
al, 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, despite having a favorable risk-benefit ratio for use with depression in adolescents and children, is not licensed for this use.
on SSRI and other antidepressant medications regarding the increased risk of suicidal behavior in patients younger than 24. Similar precautionary notice revisions were implemented by the Japanese Ministry of Health. In 2004 the Medicines and Healthcare products Regulatory Agency
in the United Kingdom issued a warning about increases in 'insomnia, agitation, weight loss, headache, tremor, loss of appetite, self harm and suicidal thoughts' when the medications are used with children and adolescents.
The introduction of a warning regarding the association between SSRIs and suicide by the FDA in 2004 led to a dramatic decrease in prescriptions of these medications to young people. Originally, there were concerns that the decrease in prescriptions caused by the warnings could increase the number of teenage suicides in the US. However, the most recent data from the US National Center for Health Statistics put these concerns to rest. The suicide rates for persons younger than 25 has actually decreased between 2004 and 2007.
and paroxetine
, and SSRI as a group have been associated with congenital malformations
, in particular, septal defects. Some evidence suggests that SSRIs are associated with neonatal complications such as neonatal abstinence syndrome (NAS) and persistent pulmonary hypertension
(PPHN).
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.
in newborn babies
. It has been documented in SSRI treatment. By November 2003, a total of 93 cases of SSRI use associated with either neonatal convulsions or withdrawal syndrome had been reported. Subsequently, the authors of a Lancet
study concluded that doctors should avoid or cautiously manage the prescribing of these drugs to pregnant women with psychiatric disorders.
when 8–21 days old, they develop behavioural changes in adulthood that resemble depression in humans. In 1997 Lundbeck found that treatment with the SSRI LU-10-134-C, which only differs from their product citalopram by two atoms could give similar results as clomipramine. Later it was found that neonatal citalopram and escitalopram makes persistent changes in the serotonergic transmission of the brain resulting in behavioral changes, which are reversed by treatment with antidepressants.
By treating normal and knockout mice
lacking the serotonin transporter with fluoxetine scientists showed that normal emotional reactions in adulthood, like a short latency to escape foot shocks and inclination to explore new environments were dependent on active serotonin transporters during the neonatal period.
But when young mice were treated with the SNRI desimipramine they developed to normal adults, which suggests that serotonin and noradrenaline have different effects in the developing brain. For humans, the developmental stage sensitive to SSRI:s corresponds with the last trimester to the first years of life. A study showed that 4-year old children perinatally exposed to SSRIs behave normally. However, the young mice and rats also seem normal until they reach puberty and develop behavioural disturbances.
The mechanism is currently unknown, but it seems that early life overstimulation of the 5HT-1 receptor that regulates serotonin production results in low serotonin production after puberty.
(PPHN) is a serious and life-threatening, but rare, lung condition that occurs soon after birth of the newborn. Newborn babies
with PPHN have high pressure in their lung blood vessel
s 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
. One study has found that PPHN is six times more common in babies whose mothers take an SSRI antidepressant after the 20th week of the pregnancy compared to babies whose mothers do not take an antidepressant.
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
, seizure
s, and cardiac toxicity
.
Treatment for SSRI overdose is mainly based on symptomatic and supportive care. Medical care may be required for agitation, maintenance of the airways, and treatment for serotonin syndrome. ECG monitoring is usually indicated to detect any cardiac abnormalities.
s). This is likely to cause severe serotonin syndrome/toxidrome
.
People taking SSRIs should also avoid taking pimozide
(an antipsychotic
diphenylbutylpiperidine derivative). Tramadol
hydrochloride (or Ultram, Ultracet) can, in rare cases, produce seizure
s when taken in conjunction with an SSRI or tricyclic antidepressant
. Liver
impairment is another contraindication for medications of this type.
SSRIs may increase blood levels and risk of toxicities of certain medications:
Certain drugs may increase toxicities of SSRIs:
Painkillers of the NSAIDs drug family may interfere and reduce efficiency of SSRIs :
SSRIs also directly interfere with ligands of 5-HT receptors, like the psychedelic
s and entactogens. SSRIs strongly attenuate the effects of tryptamine
psychedelics like psilocybin
and LSD
, and almost completely eliminate the serotonergic effects of phenethylamine
psychedelics like mescaline
and MDMA. The exact mechanism that causes this interaction is still unclear. However, salvinorin A
(found in Salvia divinorum
) has no actions at the 5-HT2A serotonin receptor, nor is it known to have affinity for any other sites to date.
after being released in synapses. How much an individual will respond to this, however, also depends on genetics. In addition, several other mechanisms are suggested for the desired effect, e.g. neuroprotection and anti-inflammatory and immunomodulatory factors. Taken together, SSRI has several advantages compared with tricyclic antidepressant
s (TCA)s and 5-HT-prodrug
s. However, the latter might be required in addition to SSRIs in certain situations.
, messages are passed between two nerve cells
via a chemical synapse
, a small gap between the cells. The (presynaptic) cell that sends the information releases neurotransmitter
s (including serotonin) into that gap. The neurotransmitters are then recognized by receptor
s 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 transporter
s into the sending (presynaptic) cell (a process called reuptake).
To stimulate the recipient cell, 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. The current model of SSRIs (the Monoamine Hypothesis) assumes that a lower homeostatic level of serotonin is primarily responsible for depression. While this holds in cases of major depression, minor to moderate cases are not as clear cut, and may in fact be caused by excess serotonin in specific areas of the brain.
Some current research points to more than just a single type of chemical signaling - the classic synapse model - involving serotonin. Astrocytes are "helper cells" in the brain that do not participate directly in chemical signaling, but play a part in homeostasis for many chemical levels in the brain. Recent research suggests that serotonin is one of the hormones regulated by astrocytes, and that astrocytes actually uptake, package, and resend serotonin in a way similar to neuronal axons, but do not have corresponding post-synaptic terminals, therefore appearing to function only to control the local levels of serotonin in the cerebrospinal fluid.
Still more research illustrates that the current model for the antidepressant activity of SSRIs may be misdirected, as a drug that works entirely opposite to SSRIs - Tianeptine
, a selective serotonin reuptake enhancer - also exhibits antidepressant activity, especially in patients resistant to SSRI therapy. The effect of an SSRE in comparison to an SSRI requires that the nature of serotonin signaling in the areas of the brain related to mood and cognition needs further elucidation. If serotonin firing is regularly phasic (related to brain waves), or rapid and discrete, then SSRIs simply compress the signal potential at affected receptors (bringing down the maximum potential and bring up the minimum) by causing a constant leftover signal (serotonin left in the synaptic gap) coupled with weaker subsequent signals (due to the decrease in presynaptic serotonin available to send new signals). By this hypothetical model, SSREs increase the signal potential separation (min to max) at affected 5-HT sites by reducing the level of free cerebrospinal serotonin and increasing the amount uptaken into axons to send new signals.
(5-hydroxytryptamine or 5-HT) into the presynaptic cell, increasing levels of 5-HT within the synaptic cleft.
However, there is one counteracting effect: high serotonin levels will not only activate the postsynaptic receptors, but also flood presynaptic autoreceptor
s, which serve as a feedback sensor for the cell. Activation of the autoreceptors (by agonist
s like serotonin) triggers a throttling of serotonin production. The resulting serotonin deficiency persists for some time, as the transporter inhibition occurs downstream to the cause of the deficiency and therefore, is not able to counterbalance the serotonin deficiency. The body adapts gradually to this situation by lowering (downregulating
) the sensitivity of the autoreceptors.
Another adaptive process provoked by SSRIs is the downregulation of postsynaptic serotonin 5-HT2A receptors
. After the use of an SSRI, since there is more serotonin available, the response is to decrease the number of postsynaptic receptors over time and in the long run, this modifies the serotonin/receptor ratio. This downregulation of 5-HT2A occurs when the antidepressant effects of SSRIs become apparent. Also, deceased suicidal and otherwise depressed patients have had more 5-HT2A receptors than normal patients. These considerations suggest that 5-HT2A overactivity is involved in the pathogenesis of depression.
Most of the serotonin receptors on the surface of the cell are coupled to a G-protein
inside it. These proteins activate or inhibit second messengers, which in turn affect transcription factor
s. Transcription factors are proteins that fit to the beginning of a gene and tell the cell to start using it.
These (slowly proceeding) neurophysiological adaptations of the brain tissue are the reason why usually several weeks of continuous SSRI use is necessary for the antidepressant effect to become fully manifested, and why increased anxiety is a common side effect in the first few days or weeks of use.
s 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. Single-nucleotide polymorphisms of the 5-HT(2A) gene correlated with paroxetine
discontinuation due to side effects in a group of elderly patients with major depression, but not mirtazapine
(a non-SSRI antidepressant) discontinuation.
s or neurogenesis
in rats. Also, SSRIs may protect against neurotoxicity caused by other compounds (for instance fenfluramine
) as well as from depression itself. SSRIs have been found to induce programmed cell death in Burkitt lymphoma and the brain tumors neuroblastoma and glioma with minimal effect on normal tissue.
processes take place during depression, mania
and bipolar disorder
, in addition to somatic
disease (such as autoimmune hypersensitivity
) and it is possible that symptoms manifest in these psychiatric illnesses are being attenuated by pharmacological effect of antidepressants on the immune system.
SSRIs have demonstrated immunomodulatory and anti-inflammatory effects against pro-inflammatory cytokine
processes, specifically on the regulation of Interferon-gamma
(IFN-gamma) and Interleukin-10 (IL-10), as well as TNF-alpha and Interleukin-6 (IL-6). Antidepressants have also been shown to suppress TH1
upregulation.
Future serotonergic antidepressants may be made to specifically target the immune system by either blocking the actions of pro-inflammatory cytokines or increasing the production of anti-inflammatory cytokines.
' 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 no significant difference in effectiveness between SSRIs and tricyclic antidepressant
s, 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 antidepressant also have a higher risk of serious cardiovascular side effects, which SSRIs lack.
, and therefore would have no effect on brain functions. Also, serotonin would activate every synapse it reaches, whereas SSRIs only enhance a signal that is already present, but too weak to come through. In addition, hope for breaching the blood-brain barrier for causes such as severe depression is underway. The selectivity of the membrane can be reduced for a drug by injecting it in a concentrated sugar solution. The high osmotic pressure of the sugar solution causes the endothelial cells of the capillaries to shrink, which opens gaps between their tight junctions and makes the barrier more permeable. As a result the drug can enter the brain tissue.
serotonin is made from tryptophan
, an amino acid
. In 1989, the Food and Drug Administration
made tryptophan available by prescription
only, in response to an outbreak of eosinophilia-myalgia syndrome
caused by impure L-tryptophan supplements sold over-the-counter
. With current standards, L-tryptophan is again available over the counter in the US as well as supplement 5-HTP, which is a direct precursor to serotonin.
. For this reason, the use of SSRIs in pediatric cases of depression is now recognized by the United States FDA as warranting a cautionary statement to the parents of children who may be prescribed SSRIs by a family doctor
. The FDA's currently required packaging insert for SSRIs includes a warning (known as a "black box warning"
) that a pooled analysis of placebo controlled trials
of 9 antidepressant drugs (including multiple SSRIs) resulted in a risk of suicidal behavior that was twice that of placebo
. At the same time, in adults SSRIs do not increase the risk of suicide.
Critics of SSRIs claim that the widely-disseminated television and print advertising of SSRIs promotes an inaccurate message, oversimplifying what these medications actually do and deceiving the public.
The criticism stems from questions about the validity of claims that SSRIs work by 'correcting' chemical imbalance
s. Without accurately measuring patients' neurotransmitter
levels to allow for continuous monitoring during treatment, it is impossible to know if one is correctly targeting a deficient neurotransmitter (i.e. correcting an imbalance), reaching a desirable level, or even introducing too much of a particular neurotransmitter. Thus it has been argued that SSRIs can actually cause chemical imbalances and abnormal brain states, as evidenced by the fact that many report problems of sexual dysfunction, whose effects last long after the medication has been discontinued. Hence, it is purported that when a patient discontinues an SSRI, they may have a chemical imbalance due to the rapid cessation of the drug that causes the discontinuation syndrome.
One possible mechanism is by inhibition of dopamine
rgic neurotransmission.
Biopsychiatrists believe that, among other factors, the balance of neurotransmitter
s in the brain
is a biological regulator of mental health
. In this theory, emotions within a "normal" spectrum reflect a proper balance of neurochemicals, but abnormally extreme emotions, such as clinical depression
, reflect an imbalance. Psychiatrists claim that medications regulate neurotransmitters, and many if not most psychiatrists also claim they treat abnormal personalities by removing a neurochemical excess or replenishing a deficit. On the other hand, Elliot Valenstein
, a psychologist and neuroscientist, claims that the broad biochemical assertions and assumptions of mainstream psychiatry are not supported by evidence.
One controversial critic of antidepressants, Peter Breggin
, a physician who opposes the overuse of prescription medications to treat patients for mental health issues, predicted iatrogenic
issues that SSRIs incur on a significant percentage of patients. Another prominent SSRI critic is David Healy
.
A widely-reported meta-analysis combined 35 clinical trials submitted to the U.S. Food and Drug Administration (FDA) before licensing of four newer antidepressants (including the SSRIs paroxetine
and fluoxetine
, and two non-SSRI antidepressants nefazodone
and venlafaxine
). The authors found that although the antidepressants were statistically superior to placebo
they did not exceed the NICE
criteria for a 'clinically significant' effect. For more detail, see the section "Efficacy".
A study in The New England Journal of Medicine on a possible publication bias
regarding the efficacy of SSRI medications in the treatment of depression suggests that their effectiveness and risk-benefit ratios may be greatly exaggerated. Of 74 studies registered with the United States FDA
, 37 with positive results were published in academic journal
s, while 22 studies with negative results were not published and 11 with negative results were published in a way that conveyed a positive outcome (one positive study was not published and three negative studies were published with results that were portrayed as negative). Overall, 94% of studies actually published were positive outcomes; when published and unpublished studies were included for analysis, the percentage of positive outcomes was 51%.
Although controversial, the existence of an SSRI-related withdrawal syndrome mimicking depression may inflate the therapeutic effect size reported in long-term (more than 6 months) placebo controlled trials of SSRI’s, due to a reliance on randomized discontinuation designs. Discontinuation trials are a variant of the classic 2-arm placebo controlled randomized controlled trials used in shorter placebo controlled studies of SSRI’s.
, for example, often allege failure to adequately warn users of potential side effects. Manufacturers have defended many suits on the merits and settled many others. In 2005, the U.S. FDA asked manufacturers to include black box warning
s on antidepressant drug packaging. The inclusion of the black box warning may have led to a decrease in prescriptions of SSRIs and an increase in suicide.
Antidepressant
An antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. According to Gelder, Mayou &*Geddes people with a depressive illness will experience a therapeutic effect to their mood;...
s in the treatment of depression, anxiety disorder
Anxiety disorder
Anxiety disorder is a blanket term covering several different forms of abnormal and pathological fear and anxiety. Conditions now considered anxiety disorders only came under the aegis of psychiatry at the end of the 19th century. Gelder, Mayou & Geddes explains that anxiety disorders are...
s, and some personality disorder
Personality disorder
Personality disorders, formerly referred to as character disorders, are a class of personality types and behaviors. Personality disorders are noted on Axis II of the Diagnostic and Statistical Manual of Mental Disorders or DSM-IV-TR of the American Psychiatric Association.Personality disorders are...
s. The efficacy of SSRIs is disputed. A 2010 meta-analysis
Meta-analysis
In statistics, a meta-analysis combines the results of several studies that address a set of related research hypotheses. In its simplest form, this is normally by identification of a common measure of effect size, for which a weighted average might be the output of a meta-analyses. Here the...
states that "The magnitude of benefit of antidepressant medication compared with placebo ... may be minimal or nonexistent, on average, in patients with mild or moderate symptoms. For patients with very severe depression, the benefit of medications over placebo is substantial." This analysis discarded a great majority of FDA-approved antidepressant studies, including those that used placebo washout periods typically used as controls.
SSRIs are believed to increase the extracellular
Extracellular
In cell biology, molecular biology and related fields, the word extracellular means "outside the cell". This space is usually taken to be outside the plasma membranes, and occupied by fluid...
level of the neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
by inhibiting
Reuptake inhibitor
A reuptake inhibitor , also known as a transporter blocker, is a drug that inhibits the plasmalemmal transporter-mediated reuptake of a neurotransmitter from the synapse into the pre-synaptic neuron, leading to an increase in the extracellular concentrations of the neurotransmitter and therefore an...
its reuptake
Reuptake
Reuptake, or re-uptake, is the reabsorption of a neurotransmitter by a neurotransmitter transporter of a pre-synaptic neuron after it has performed its function of transmitting a neural impulse....
into the presynaptic cell, increasing the level of serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
in the synaptic cleft available to bind to the postsynaptic receptor. They have varying degrees of selectivity for the other monoamine transporter
Monoamine transporter
Monoamine transporters are protein structures that function as integral plasma membrane transporters to regulate concentrations of extracellular monoamine neurotransmitters. Three major classes of MATs are responsible for the reuptake of their associated amine neurotransmitters...
s, with pure SSRIs having only weak affinity for the noradrenaline
Norepinephrine transporter
The norepinephrine transporter , also known as solute carrier family 6 member 2 , is a protein that in humans is encoded by the SLC6A2 gene....
and dopamine transporter
Dopamine transporter
The dopamine transporter is a membrane-spanning protein that pumps the neurotransmitter dopamine out of the synapse back into cytosol, from which other transporters sequester DA and NE into vesicles for later storage and release...
.
SSRIs are the first class of psychotropic drugs discovered using the process called rational drug design, a process that starts with a specific biological target and then creates a molecule designed to affect it. They are the most widely prescribed antidepressants in many countries.
Medical uses
The main indication for SSRIs is clinical depressionClinical depression
Major depressive disorder is a mental disorder characterized by an all-encompassing low mood accompanied by low self-esteem, and by loss of interest or pleasure in normally enjoyable activities...
. SSRIs are frequently prescribed for anxiety disorder
Anxiety disorder
Anxiety disorder is a blanket term covering several different forms of abnormal and pathological fear and anxiety. Conditions now considered anxiety disorders only came under the aegis of psychiatry at the end of the 19th century. Gelder, Mayou & Geddes explains that anxiety disorders are...
s, such as social anxiety
Social anxiety
Social anxiety is anxiety about social situations, interactions with others, and being evaluated or scrutinized by other people...
, panic disorder
Panic disorder
Panic disorder is an anxiety disorder characterized by recurring severe panic attacks. It may also include significant behavioral change lasting at least a month and of ongoing worry about the implications or concern about having other attacks. The latter are called anticipatory attacks...
s, obsessive–compulsive disorder (OCD), eating disorder
Eating disorder
Eating disorders refer to a group of conditions defined by abnormal eating habits that may involve either insufficient or excessive food intake to the detriment of an individual's physical and mental health. Bulimia nervosa, anorexia nervosa, and binge eating disorder are the most common specific...
s, chronic pain
Chronic pain
Chronic pain has several different meanings in medicine. Traditionally, the distinction between acute and chronic pain has relied upon an arbitrary interval of time from onset; the two most commonly used markers being 3 months and 6 months since the initiation of pain, though some theorists and...
and occasionally, for posttraumatic stress disorder (PTSD). They are also frequently used to treat depersonalization disorder
Depersonalization disorder
Depersonalization disorder is a dissociative disorder in which the sufferer is affected by persistent or recurrent feelings of depersonalization and/or derealization. Diagnostic criteria include persistent or recurrent experiences of feeling detached from one's mental processes or body...
, although generally with poor results . Though not specifically indicated by the manufacturers, they are sometimes prescribed to treat irritable bowel syndrome
Irritable bowel syndrome
Irritable bowel syndrome is a diagnosis of exclusion. It is a functional bowel disorder characterized by chronic abdominal pain, discomfort, bloating, and alteration of bowel habits in the absence of any detectable organic cause. In some cases, the symptoms are relieved by bowel movements...
(IBS), Lichen simplex chronicus
Lichen simplex chronicus
Lichen simplex chronicus is a skin disorder characterized by chronic itching and scratching. The constant scratching causes thick, leathery, brownish skin.- Causes :...
and premature ejaculation
Premature ejaculation
Premature ejaculation is a condition in which a man ejaculates earlier than he or his partner would like him to. Premature ejaculation is also known as rapid ejaculation, rapid climax, premature climax, or early ejaculation....
.
All SSRIs are approved in the U.S. for use with psychiatric disorders as outlined in the Diagnostic and Statistical Manual of Mental Disorders
Diagnostic and Statistical Manual of Mental Disorders
The Diagnostic and Statistical Manual of Mental Disorders is published by the American Psychiatric Association and provides a common language and standard criteria for the classification of mental disorders...
(DSM IV).
Approved uses for SSRIs vary by country and are determined by the overseeing branch of government in charge of regulating drugs. In the U.S., the Food and Drug Administration (FDA) approves drugs after trial results have been submitted by the pharmaceutical companies. In Europe, drugs can be approved either by the European Medicines Agency
European Medicines Agency
The European Medicines Agency is a European agency for the evaluation of medicinal products. From 1995 to 2004, the European Medicines Agency was known as European Agency for the Evaluation of Medicinal Products.Roughly parallel to the U.S...
for human consumption throughout the European Union
European Union
The European Union is an economic and political union of 27 independent member states which are located primarily in Europe. The EU traces its origins from the European Coal and Steel Community and the European Economic Community , formed by six countries in 1958...
or by the regulatory agencies of individual countries for use within those countries.. In Canada, the drug approval process is carried out by Health Canada
Health Canada
Health Canada is the department of the government of Canada with responsibility for national public health.The current Minister of Health is Leona Aglukkaq, a Conservative Member of Parliament appointed to the position by Prime Minister Stephen Harper.-Branches, regions and agencies:Health Canada...
.
A general disadvantage of SSRIs in treating premature ejaculation is that they require continuous daily treatment to delay ejaculation significantly. For the occasional "on-demand" treatment, a few hours before coitus, clomipramine
Clomipramine
Clomipramine is a tricyclic antidepressant . It was developed in the 1960s by the Swiss drug manufacturer Geigy and has been in clinical use worldwide ever since.- Indications :...
gave better results than paroxetine in one study, while in another study both sertraline and clomipramine were indistinguishable from the pause–squeeze technique and inferior to paroxetine. The most recent research, conducted in 2007, suggests that on-demand treatment with sildenafil
Sildenafil
Sildenafil citrate, sold as Viagra, Revatio and under various other trade names, is a drug used to treat erectile dysfunction and pulmonary arterial hypertension . It was originally developed by British scientists and then brought to market by the US-based pharmaceutical company Pfizer...
(Viagra) offers a dramatic improvement in ejaculation delay and sexual satisfaction as compared with daily paroxetine, with on-demand sertraline, paroxetine or clomipramine, and with the pause–squeeze technique.
Efficacy
Efficacy of SSRIs for the treatment of depression compared to placebo is disputed. Two meta-analyses of clinical trials found that in mild and moderate depression, which constitute the vast majority of depression cases, the effect of SSRI is very small or none compared to placebo, while in very severe depression the effect of SSRIs is clinically significant. However, treatment by either placebo or SSRI may have a significant effect in lower-severity depression vs. no treatment at all.A widely-reported 2008 meta-analysis combined 35 clinical trials submitted to the U.S. Food and Drug Administration (FDA) before licensing of four newer antidepressants (including the SSRIs paroxetine
Paroxetine
Paroxetine is an SSRI antidepressant. Marketing of the drug began in 1992 by the pharmaceutical company SmithKline Beecham, now GlaxoSmithKline...
and fluoxetine
Fluoxetine
Fluoxetine is an antidepressant of the selective serotonin reuptake inhibitor class. It is manufactured and marketed by Eli Lilly and Company...
, and two non-SSRI antidepressants nefazodone
Nefazodone
Nefazodone is an antidepressant marketed by Bristol-Myers Squibb. Its sale was discontinued in 2003 in some countries due to the rare incidence of hepatotoxicity , which could lead to the need for a liver transplant, or even death. The incidence of severe liver damage is approximately 1 in every...
and venlafaxine
Venlafaxine
Venlafaxine is an antidepressant of the serotonin-norepinephrine reuptake inhibitor class. First introduced by Wyeth in 1993, now marketed by Pfizer, it is licensed for the treatment of major depressive disorder , as a treatment for generalized anxiety disorder, and comorbid indications in...
). The authors found that although the effect of antidepressants vs placebo
Placebo
A placebo is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient...
s was statistically significant
Statistical significance
In statistics, a result is called statistically significant if it is unlikely to have occurred by chance. The phrase test of significance was coined by Ronald Fisher....
, it did not exceed the NICE
NICE
NICE may refer to:* National Independent Cadres and Elites in Iraq* National Institute for Coordinated Experiments, a fictional organisation in C.S...
criteria for a clinically significant effect. In particular they found that the effect size
Effect size
In statistics, an effect size is a measure of the strength of the relationship between two variables in a statistical population, or a sample-based estimate of that quantity...
was very small for moderate depression but increased with severity reaching 'clinical significance' for very severe depression. The relationship between severity and efficacy was attributed 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 but even when they re-analyse the data they find that this is still below the NICE threshold for 'clinical significance' when all results are combined (although individually paroxetine and venflafaxine exceed this threshold).
A 2010 meta-analysis reached similar conclusions: in mild and moderate depression, specifically that the effect of SSRI is very small or none compared to placebo, while it is clinically significant in very severe depression.
List of agents
Drugs in this class include (trade names in parentheses):- citalopramCitalopramCitalopram brand names: Celexa, Cipramil) is an antidepressant drug of the selective serotonin reuptake inhibitor class. It has U.S...
(Celexa, Cipramil, Cipram, Dalsan, Recital, Emocal, Sepram, Seropram, Citox, Cital) - dapoxetineDapoxetineDapoxetine is a short-acting selective serotonin reuptake inhibitor marketed for the treatment of premature ejaculation in men. Dapoxetine is the only drug with regulatory approval for such an indication. Currently, it is approved in several European countries, including Finland, Sweden,...
(Priligy) - escitalopramEscitalopramEscitalopram is an antidepressant of the selective serotonin reuptake inhibitor class. It is approved by the U.S...
(Lexapro, Cipralex, Seroplex, Esertia) - fluoxetineFluoxetineFluoxetine is an antidepressant of the selective serotonin reuptake inhibitor class. It is manufactured and marketed by Eli Lilly and Company...
(Prozac, Fontex, Seromex, Seronil, Sarafem, Ladose, Motivest, Flutop, Fluctin (EUR), Fluox (NZ), Depress (UZB), Lovan (AUS), Prodep (IND)) - fluvoxamineFluvoxamineFluvoxamine is an antidepressant which functions as a selective serotonin reuptake inhibitor . Fluvoxamine was first approved by the U.S. Food and Drug Administration in 1993 for the treatment of obsessive compulsive disorder . Fluvoxamine CR is approved to treat social anxiety disorder...
(Luvox, Fevarin, Faverin, Dumyrox, Favoxil, Movox) - indalpineIndalpineIndalpine is an SSRI class drug that was discovered in 1977 by the pharmacologists Le Fur and Uzan at Pharmuka, a small Paris based pharmaceutical firm, who credit Baron Shopsin and the innovative body of basic and clinical research carried out with colleagues at NYU-Bellevue/NYU School of...
(Upstene) (discontinued) - paroxetineParoxetineParoxetine is an SSRI antidepressant. Marketing of the drug began in 1992 by the pharmaceutical company SmithKline Beecham, now GlaxoSmithKline...
(Paxil, Seroxat, Sereupin, Aropax, Deroxat, Divarius, Rexetin, Xetanor, Paroxat, Loxamine, Deparoc) - sertralineSertralineSertraline hydrochloride is an antidepressant of the selective serotonin reuptake inhibitor class. It was introduced to the market by Pfizer in 1991. Sertraline is primarily used to treat major depression in adult outpatients as well as obsessive–compulsive, panic, and social anxiety disorders in...
(Zoloft, Lustral, Serlain, Asentra) - vilazodoneVilazodoneVilazodone is an SSRI antidepressant developed by Clinical Data for the treatment of major depressive disorder. The chemical compound was originally developed by Merck KGaA ....
(Viibryd) - zimelidineZimelidineZimelidine was the first selective serotonin reuptake inhibitor antidepressant to be marketed. It is a pyridylallylamine, and is structurally different from other antidepressants....
(Zelmid, Normud) (discontinued)
Related agents
SSRIs form a subclass of serotonin uptake inhibitors, which includes other non-selective inhibitors as well. Serotonin-norepinephrine reuptake inhibitorSerotonin-norepinephrine reuptake inhibitor
Serotonin–norepinephrine reuptake inhibitors are a class of antidepressant drugs used in the treatment of major depression and other mood disorders...
s, serotonin-norepinephrine-dopamine reuptake inhibitors and selective serotonin reuptake enhancer
Selective serotonin reuptake enhancer
A selective serotonin reuptake enhancer is a type of drug which enhances the plasmalemmal reuptake of the neurotransmitter serotonin, leading to a decrease in its synaptic concentrations and therefore a decrease in serotonergic neurotransmission....
s are also serotonergic
Serotonergic
Serotonergic or serotoninergic means "related to the neurotransmitter serotonin". A synapse is serotonergic if it uses serotonin as its neurotransmitter...
antidepressants.
Adverse effects
General side effects are mostly present during the first 1–4 weeks while the body adapts to the drug (with the exception of sexual side effects, which tend to occur later in treatment). In fact, it often takes 6–8 weeks for the drug to begin reaching its full potential (the slow onset is considered a downside to treatment with SSRIs). Almost all SSRIs are known to cause one or more of these symptoms:- anhedoniaAnhedoniaIn psychology and psychiatry, anhedonia is defined as the inability to experience pleasure from activities usually found enjoyable, e.g. hobbies, exercise, social interaction or sexual activity....
- apathyApathyApathy is a state of indifference, or the suppression of emotions such as concern, excitement, motivation and passion. An apathetic individual has an absence of interest in or concern about emotional, social, spiritual, philosophical or physical life.They may lack a sense of purpose or meaning in...
- nauseaNauseaNausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
/vomiting - drowsiness or somnolenceSomnolenceSomnolence is a state of near-sleep, a strong desire for sleep, or sleeping for unusually long periods . It has two distinct meanings, referring both to the usual state preceding falling asleep, and the chronic condition referring to being in that state independent of a circadian rhythm...
- headacheHeadacheA headache or cephalalgia is pain anywhere in the region of the head or neck. It can be a symptom of a number of different conditions of the head and neck. The brain tissue itself is not sensitive to pain because it lacks pain receptors. Rather, the pain is caused by disturbance of the...
- bruxismBruxismBruxism is characterized by the grinding of the teeth and typically includes the clenching of the jaw. It is an oral parafunctional activity that occurs in most humans at some time in their lives. In most people, bruxism is mild enough not to be a health problem...
- tinnitusTinnitusTinnitus |ringing]]") is the perception of sound within the human ear in the absence of corresponding external sound.Tinnitus is not a disease, but a symptom that can result from a wide range of underlying causes: abnormally loud sounds in the ear canal for even the briefest period , ear...
- extremely vivid or strange dreamDreamDreams are successions of images, ideas, emotions, and sensations that occur involuntarily in the mind during certain stages of sleep. The content and purpose of dreams are not definitively understood, though they have been a topic of scientific speculation, philosophical intrigue and religious...
s - dizzinessDizzinessDizziness refers to an impairment in spatial perception and stability. The term is somewhat imprecise. It can be used to mean vertigo, presyncope, disequilibrium, or a non-specific feeling such as giddiness or foolishness....
- fatigue
- mydriasisMydriasisMydriasis is a dilation of the pupil due to disease, trauma or the use of drugs. Normally, the pupil dilates in the dark and constricts in the light to respectively improve vividity at night and to protect the retina from sunlight damage during the day...
(pupil dilation) - urinary retentionUrinary retentionUrinary retention, also known as ischuria, is a lack of ability to urinate. It is a common complication of benign prostatic hyperplasia , although it can also be caused by nerve dysfunction, constipation, infection, or medications...
- changes in appetite
- insomniaInsomniaInsomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...
and/or changes in sleep - weight lossWeight lossWeight loss, in the context of medicine, health or physical fitness, is a reduction of the total body mass, due to a mean loss of fluid, body fat or adipose tissue and/or lean mass, namely bone mineral deposits, muscle, tendon and other connective tissue...
/gain (measured by a change in bodyweight of 7 pounds) - increased risk of bone fractureBone fractureA bone fracture is a medical condition in which there is a break in the continuity of the bone...
s and injuries - changes in sexual behaviourHuman sexual behaviorHuman sexual activities or human sexual practices or human sexual behavior refers to the manner in which humans experience and express their sexuality. People engage in a variety of sexual acts from time to time, and for a wide variety of reasons...
(see the next section) - increased feelings of depression and anxiety (which may sometimes provoke panic attackPanic attackPanic attacks are periods of intense fear or apprehension that are of sudden onset and of relatively brief duration. Panic attacks usually begin abruptly, reach a peak within 10 minutes, and subside over the next several hours...
s) - maniaManiaMania, the presence of which is a criterion for certain psychiatric diagnoses, is a state of abnormally elevated or irritable mood, arousal, and/ or energy levels. In a sense, it is the opposite of depression...
and psychotic disorders - tremorTremorA tremor is an involuntary, somewhat rhythmic, muscle contraction and relaxation involving to-and-fro movements of one or more body parts. It is the most common of all involuntary movements and can affect the hands, arms, eyes, face, head, vocal folds, trunk, and legs. Most tremors occur in the...
s (and other symptoms of Parkinsonism in vulnerable elderly patients) - autonomicAutonomic nervous systemThe autonomic nervous system is the part of the peripheral nervous system that acts as a control system functioning largely below the level of consciousness, and controls visceral functions. The ANS affects heart rate, digestion, respiration rate, salivation, perspiration, diameter of the pupils,...
dysfunction including orthostatic hypotensionOrthostatic hypotensionOrthostatic hypotension, also known as postural hypotension, orthostasis, and colloquially as head rush or dizzy spell, is a form of hypotension in which a person's blood pressure suddenly falls when the person stands up or stretches. The decrease is typically greater than 20/10 mm Hg, and may be...
, increased or reduced sweatingSweatingPerspiration is the production of a fluid consisting primarily of water as well as various dissolved solids , that is excreted by the sweat glands in the skin of mammals... - akathisiaAkathisiaAkathisia, or acathisia, is a syndrome characterized by unpleasant sensations of inner restlessness that manifests itself with an inability to sit still or remain motionless...
- renal impairmentRenal failureRenal failure or kidney failure describes a medical condition in which the kidneys fail to adequately filter toxins and waste products from the blood...
- suicidal ideationSuicidal ideationSuicidal ideation is a common medical term for thoughts about suicide, which may be as detailed as a formulated plan, without the suicidal act itself. Although most people who undergo suicidal ideation do not commit suicide, some go on to make suicide attempts...
(thoughts of suicideSuicideSuicide is the act of intentionally causing one's own death. Suicide is often committed out of despair or attributed to some underlying mental disorder, such as depression, bipolar disorder, schizophrenia, alcoholism, or drug abuse...
) - photosensitivityPhotosensitivityPhotosensitivity is the amount to which an object reacts upon receiving photons, especially visible light.- Human medicine :Sensitivity of the skin to a light source can take various forms. People with particular skin types are more sensitive to sunburn...
- ParesthesiaParesthesiaParesthesia , spelled "paraesthesia" in British English, is a sensation of tingling, burning, pricking, or numbness of a person's skin with no apparent long-term physical effect. It is more generally known as the feeling of "pins and needles" or of a limb "falling asleep"...
- dissociative disordersDissociative disordersDissociative disorders are defined as conditions that involve disruptions or breakdowns of memory, awareness, identity and/or perception. See also dissociation. People with dissociative disorders are able to escape from reality involuntarily...
, cognitive disorders and loss of contact with reality - Syndrome of inappropriate antidiuretic hormone hypersecretion
Many side effects disappear after the adaptation phase, when the antidepressant effects begin to come to prominence. However, despite being called general, the side effects and their durations are highly individual and drug-specific. Usually the treatment is begun with a small dose to see how the patient's body reacts to the drug, after that either the dose can be adjusted (e.g. Prozac in the UK is begun at a 20 mg dose, and then adjusted as necessary to 40 mg or 60 mg). Should the drug prove ineffective, or the side effects intolerable to the patient, another common route is to switch treatment to either another SSRI, or an SNRI
Serotonin-norepinephrine reuptake inhibitor
Serotonin–norepinephrine reuptake inhibitors are a class of antidepressant drugs used in the treatment of major depression and other mood disorders...
.
Mania
Mania
Mania, the presence of which is a criterion for certain psychiatric diagnoses, is a state of abnormally elevated or irritable mood, arousal, and/ or energy levels. In a sense, it is the opposite of depression...
or hypomania
Hypomania
Hypomania is a mood state characterized by persistent and pervasive elevated or irritable mood, as well as thoughts and behaviors that are consistent with such a mood state...
is a possible side effect. Users with some type of bipolar disorder
Bipolar disorder
Bipolar disorder or bipolar affective disorder, historically known as manic–depressive disorder, is a psychiatric diagnosis that describes a category of mood disorders defined by the presence of one or more episodes of abnormally elevated energy levels, cognition, and mood with or without one or...
are at a much higher risk, however SSRI-induced mania in patients previously diagnosed with unipolar depression can trigger a bipolar diagnosis.
Sexual side effects
SSRIs can cause various types of sexual dysfunctionSexual dysfunction
Sexual dysfunction or sexual malfunction refers to a difficulty experienced by an individual or a couple during any stage of a normal sexual activity, including desire, arousal or orgasm....
such as anorgasmia
Anorgasmia
Anorgasmia, or Coughlan's syndrome, is a type of sexual dysfunction in which a person cannot achieve orgasm, even with adequate stimulation. In males the condition is often related to delayed ejaculation . Anorgasmia can often cause sexual frustration...
, erectile dysfunction
Erectile dysfunction
Erectile dysfunction is sexual dysfunction characterized by the inability to develop or maintain an erection of the penis during sexual performance....
, and diminished libido
Libido
Libido refers to a person's sex drive or desire for sexual activity. The desire for sex is an aspect of a person's sexuality, but varies enormously from one person to another, and it also varies depending on circumstances at a particular time. A person who has extremely frequent or a suddenly...
. Initial studies found sexual side effects not significantly different from placebo, but since these studies relied on unprompted reporting, the frequency was probably underestimated. In more recent studies, doctors have specifically asked about sexual difficulties, and found that they are present in between 17% and 41% of patients, although the lack of placebo control in these studies means they are likely overestimates.
Stimulation of postsynaptic 5-HT2 and 5-HT3 receptors decreases dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
and norepinephrine release from the substantia nigra
Substantia nigra
The substantia nigra is a brain structure located in the mesencephalon that plays an important role in reward, addiction, and movement. Substantia nigra is Latin for "black substance", as parts of the substantia nigra appear darker than neighboring areas due to high levels of melanin in...
. A number of drugs are not associated with sexual side effects (such as bupropion
Bupropion
Bupropion is an atypical antidepressant and smoking cessation aid. The drug is a non-tricyclic antidepressant and differs from most commonly prescribed antidepressants such as SSRIs, as its primary pharmacological action is thought to be norepinephrine-dopamine reuptake inhibition...
, mirtazapine
Mirtazapine
Mirtazapine is a tetracyclic antidepressant used primarily in the treatment of depression. It is also sometimes used as a hypnotic, antiemetic, and appetite stimulant, and for the treatment of anxiety, among other indications...
and maprotiline
Maprotiline
Maprotiline is a tetracyclic antidepressant . It is a strong norepinephrine reuptake inhibitor with only weak effects on serotonin and dopamine reuptake....
, some of which are also not associated with weight gain). As a result, sexual dysfunction caused by SSRIs can sometimes be mitigated by several different drugs. These include:
- bupropionBupropionBupropion is an atypical antidepressant and smoking cessation aid. The drug is a non-tricyclic antidepressant and differs from most commonly prescribed antidepressants such as SSRIs, as its primary pharmacological action is thought to be norepinephrine-dopamine reuptake inhibition...
(norepinephrineNorepinephrine reuptake inhibitorA norepinephrine reuptake inhibitor or adrenergic reuptake inhibitor , is a type of drug which acts as a reuptake inhibitor for the neurotransmitters norepinephrine and epinephrine by blocking the action of the norepinephrine transporter...
and dopamine reuptake inhibitorDopamine reuptake inhibitorA dopamine reuptake inhibitor is a type of drug that acts as a reuptake inhibitor for the neurotransmitter dopamine by blocking the action of the dopamine transporter...
) - buspironeBuspironeBuspirone is an anxiolytic psychoactive drug of the azapirone chemical class, and is primarily used to treat generalized anxiety disorder Bristol-Myers Squibb gained FDA approval of buspirone in 1986 for treatment of GAD...
(serotoninSerotoninSerotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
5-HT1A receptor5-HT1A receptorThe 5-HT1A receptor is a subtype of 5-HT receptor that binds the endogenous neurotransmitter serotonin . It is a G protein-coupled receptor that is coupled to Gi/Go and mediates inhibitory neurotransmission...
partial agonistPartial agonistPartial agonists bind and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist...
) - cyproheptadineCyproheptadineCyproheptadine , sold under the brand name Periactin, is a first-generation antihistamine with additional anticholinergic, antiserotonergic, and local anesthetic properties.- Indications :...
(5-HT2 antagonist) - methylphenidateMethylphenidateMethylphenidate is a psychostimulant drug approved for treatment of attention-deficit hyperactivity disorder, postural orthostatic tachycardia syndrome and narcolepsy. It may also be prescribed for off-label use in treatment-resistant cases of lethargy, depression, neural insult and obesity...
(stimulant) - mirtazapineMirtazapineMirtazapine is a tetracyclic antidepressant used primarily in the treatment of depression. It is also sometimes used as a hypnotic, antiemetic, and appetite stimulant, and for the treatment of anxiety, among other indications...
(noradrenergic and specific serotonergic antidepressantNoradrenergic and specific serotonergic antidepressantNoradrenergic and specific serotonergic antidepressants are a class of psychiatric drugs used primarily as antidepressants. They act by antagonizing various adrenergic and serotonin receptors, of which typically consist of α1-adrenergic and α2-adrenergic, and 5-HT2A, 5-HT2C, and 5-HT3, respectively...
(NaSSA)) - amphetamineAmphetamineAmphetamine or amfetamine is a psychostimulant drug of the phenethylamine class which produces increased wakefulness and focus in association with decreased fatigue and appetite.Brand names of medications that contain, or metabolize into, amphetamine include Adderall, Dexedrine, Dextrostat,...
(stimulant) - amantadineAmantadineAmantadine is the organic compound known formally as 1-adamantylamine or 1-aminoadamantane. The molecule consists of adamantane backbone that has an amino group substituted at one of the four methyne positions. This pharmaceutical is sold under the name Symmetrel for use both as an antiviral and an...
(antiviral drugAntiviral drugAntiviral drugs are a class of medication used specifically for treating viral infections. Like antibiotics for bacteria, specific antivirals are used for specific viruses...
) - pramipexolePramipexolePramipexole is a non-ergoline dopamine agonist indicated for treating early-stage Parkinson's disease and restless legs syndrome...
(dopamine agonistDopamine agonistA dopamine agonist is a compound that activates dopamine receptors in the absence of dopamine. Dopamine agonists activate signaling pathways through the dopamine receptor and trimeric G-proteins, ultimately leading to changes in gene transcription.-Uses:...
) and - ropiniroleRopiniroleRopinirole is a non-ergoline dopamine agonist. It is manufactured by GlaxoSmithKline , Cipla and Sun Pharmaceutical. It is used in the treatment of Parkinson's disease...
(dopamine agonistDopamine agonistA dopamine agonist is a compound that activates dopamine receptors in the absence of dopamine. Dopamine agonists activate signaling pathways through the dopamine receptor and trimeric G-proteins, ultimately leading to changes in gene transcription.-Uses:...
)
On the other hand, the effect of SSRIs to slow down sexual stimulation may be used as treatment; SSRIs have been proposed as a drug to treat premature ejaculation
Premature ejaculation
Premature ejaculation is a condition in which a man ejaculates earlier than he or his partner would like him to. Premature ejaculation is also known as rapid ejaculation, rapid climax, premature climax, or early ejaculation....
.
Cardiovascular side effects
Cardiovascular side effects are very rare with SSRI use, with a reported incidenceIncidence (epidemiology)
Incidence is a measure of the risk of developing some new condition within a specified period of time. Although sometimes loosely expressed simply as the number of new cases during some time period, it is better expressed as a proportion or a rate with a denominator.Incidence proportion is the...
of less than 0.0003 percent. SSRIs inhibit cardiac and vascular sodium, calcium
Calcium channel
A Calcium channel is an ion channel which displays selective permeability to calcium ions. It is sometimes synonymous as voltage-dependent calcium channel, although there are also ligand-gated calcium channels.-Comparison tables:...
and potassium channel
Potassium channel
In the field of cell biology, potassium channels are the most widely distributed type of ion channel and are found in virtually all living organisms. They form potassium-selective pores that span cell membranes...
s and prolong QT interval
QT interval
In cardiology, the QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle. In general, the QT interval represents electrical depolarization and repolarization of the left and right ventricles...
s. However, a number of large studies of patients without known pre-existing heart disease have reported no EKG
Electrocardiogram
Electrocardiography is a transthoracic interpretation of the electrical activity of the heart over a period of time, as detected by electrodes attached to the outer surface of the skin and recorded by a device external to the body...
changes related to SSRI use. In overdose, fluoxetine has been reported to cause sinus tachycardia
Sinus tachycardia
Sinus tachycardia is a heart rhythm with elevated rate of impulses originating from the sinoatrial node, defined as a rate greater than 100 beats/min in an average adult. The normal heart rate in the average adult ranges from 60–100 beats/min...
, myocardial infarction
Myocardial infarction
Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...
, junctional rhythm
Junctional rhythm
Junctional rhythm describes an abnormal heart rhythm resulting from impulses coming from a locus of tissue in the area of the atrioventricular node, the "junction" between atria and ventricles....
s and trigeminy. Some authors have suggested electrocardiographic
Electrocardiogram
Electrocardiography is a transthoracic interpretation of the electrical activity of the heart over a period of time, as detected by electrodes attached to the outer surface of the skin and recorded by a device external to the body...
monitoring in patients with severe pre-existing cardiovascular disease who are taking SSRI's.
Discontinuation syndrome
AntidepressantAntidepressant
An antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. According to Gelder, Mayou &*Geddes people with a depressive illness will experience a therapeutic effect to their mood;...
s such as SSRIs have some dependence
Substance dependence
The section about substance dependence in the Diagnostic and Statistical Manual of Mental Disorders does not use the word addiction at all. It explains:...
producing effects, most notably a withdrawal syndrome
SSRI discontinuation syndrome
SSRI discontinuation syndrome, also known as SSRI withdrawal syndrome or SSRI cessation syndrome, is a syndrome that can occur following the interruption, dose reduction, or discontinuation of SSRI or SNRI antidepressant medications...
. Their dependence producing properties (depending on the antidepressant) may not be as significant as other psychotropic drugs such as benzodiazepine
Benzodiazepine
A benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
s; however, withdrawal symptoms nonetheless may be quite severe and even debilitating. SSRIs have little abuse
Drug abuse
Substance abuse, also known as drug abuse, refers to a maladaptive pattern of use of a substance that is not considered dependent. The term "drug abuse" does not exclude dependency, but is otherwise used in a similar manner in nonmedical contexts...
potential, but discontinuation can produce disturbing withdrawal symptoms that may be indistinguishable from a reoccurrence of the original illness. Since physical dependence
Physical dependence
Physical dependence refers to a state resulting from chronic use of a drug that has produced tolerance and where negative physical symptoms of withdrawal result from abrupt discontinuation or dosage reduction...
is a reality, discontinuation should be discussed with a medical practitioner before beginning treatment with this class of drugs.
When discontinuing an SSRI or SNRI some doctors may switch the patient to fluoxetine
Fluoxetine
Fluoxetine is an antidepressant of the selective serotonin reuptake inhibitor class. It is manufactured and marketed by Eli Lilly and Company...
due to its much longer half-life
Biological half-life
The biological half-life or elimination half-life of a substance is the time it takes for a substance to lose half of its pharmacologic, physiologic, or radiologic activity, as per the MeSH definition...
. This may avoid many of the severe withdrawal symptoms associated with SSRI/SNRI discontinuation. This can be done either by administering a single 20 mg dose of fluoxetine
Fluoxetine
Fluoxetine is an antidepressant of the selective serotonin reuptake inhibitor class. It is manufactured and marketed by Eli Lilly and Company...
or by beginning on a low dosage of fluoxetine
Fluoxetine
Fluoxetine is an antidepressant of the selective serotonin reuptake inhibitor class. It is manufactured and marketed by Eli Lilly and Company...
and slowly tapering down. Any SSRI or SNRI may be requested in liquid form, which allows very gradual tapering. Alternatively, a patient wishing to stop taking an SSRI/SNRI may visit a compounding pharmacy where his or her prescription may be re-arranged into progressively smaller dosages. For example the lowest dose of cymbalta that can normally be prescribed is 20 mg in gel capsules; a compounding pharmacist may divide this into doses of 20, 15, 10, 5 and 2.5 mg so that a proper tapered reduction may take place.
Post-SSRI sexual dysfunction
According to one source, Post-SSRI sexual dysfunction (PSSD) is an iatrogenic type of sexual dysfunctionSexual dysfunction
Sexual dysfunction or sexual malfunction refers to a difficulty experienced by an individual or a couple during any stage of a normal sexual activity, including desire, arousal or orgasm....
caused directly by the previous use of SSRI antidepressant
Antidepressant
An antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. According to Gelder, Mayou &*Geddes people with a depressive illness will experience a therapeutic effect to their mood;...
s.
While apparently uncommon, it can last for months, years, or sometimes indefinitely after the discontinuation of SSRIs.
One or more of the following sexual
Human sexuality
Human sexuality is the awareness of gender differences, and the capacity to have erotic experiences and responses. Human sexuality can also be described as the way someone is sexually attracted to another person whether it is to opposite sexes , to the same sex , to either sexes , or not being...
symptoms may persist or begin after the discontinuation of SSRIs:
- Decreased or absent libidoLibidoLibido refers to a person's sex drive or desire for sexual activity. The desire for sex is an aspect of a person's sexuality, but varies enormously from one person to another, and it also varies depending on circumstances at a particular time. A person who has extremely frequent or a suddenly...
- Impotence or reduced vaginal lubricationVaginal lubricationVaginal lubrication is a lubricating fluid that is naturally produced in a woman's vagina. Vaginal lubrication or moistness is present at all times, but production increases significantly during a woman's sexual arousal in anticipation of sexual intercourse...
- Difficulty initiating or maintaining an erectionErectionPenile erection is a physiological phenomenon where the penis becomes enlarged and firm. Penile erection is the result of a complex interaction of psychological, neural, vascular and endocrine factors, and is usually, though not exclusively, associated with sexual arousal...
or becoming aroused - Persistent genital arousal disorder despite absence of desire
- Muted, delayed or absent orgasmOrgasmOrgasm is the peak of the plateau phase of the sexual response cycle, characterized by an intense sensation of pleasure...
(anorgasmiaAnorgasmiaAnorgasmia, or Coughlan's syndrome, is a type of sexual dysfunction in which a person cannot achieve orgasm, even with adequate stimulation. In males the condition is often related to delayed ejaculation . Anorgasmia can often cause sexual frustration...
) - Reduced or no experience of pleasure during orgasmOrgasmOrgasm is the peak of the plateau phase of the sexual response cycle, characterized by an intense sensation of pleasure...
(ejaculatory anhedoniaAnhedoniaIn psychology and psychiatry, anhedonia is defined as the inability to experience pleasure from activities usually found enjoyable, e.g. hobbies, exercise, social interaction or sexual activity....
) - Premature ejaculationPremature ejaculationPremature ejaculation is a condition in which a man ejaculates earlier than he or his partner would like him to. Premature ejaculation is also known as rapid ejaculation, rapid climax, premature climax, or early ejaculation....
- Weakened penile, vaginaVaginaThe vagina is a fibromuscular tubular tract leading from the uterus to the exterior of the body in female placental mammals and marsupials, or to the cloaca in female birds, monotremes, and some reptiles. Female insects and other invertebrates also have a vagina, which is the terminal part of the...
l or clitoral sensitivity - Genital anesthesiaAnesthesiaAnesthesia, or anaesthesia , traditionally meant the condition of having sensation blocked or temporarily taken away...
- Loss or decreased response to sexualHuman sexualityHuman sexuality is the awareness of gender differences, and the capacity to have erotic experiences and responses. Human sexuality can also be described as the way someone is sexually attracted to another person whether it is to opposite sexes , to the same sex , to either sexes , or not being...
stimuli - Reduced semenSemenSemen is an organic fluid, also known as seminal fluid, that may contain spermatozoa. It is secreted by the gonads and other sexual organs of male or hermaphroditic animals and can fertilize female ova...
volume - PriapismPriapismPriapism is a potentially harmful and painful medical condition in which the erect penis or clitoris does not return to its flaccid state, despite the absence of both physical and psychological stimulation, within four hours. There are two types of priapism: low-flow and high-flow. Low-flow...
(persistent erectile state of the penis or clitoris)
Children and adolescents
Several studies have found that SSRI can cause a higher risk of suicidal behavior in children and adolescents. For instance, a 2004 U.S. Food and Drug Administration (FDA) analysis of clinical trialClinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
s on children with major depressive disorder found statistically significant increases of the risks of "possible suicidal ideation
Suicidal ideation
Suicidal ideation is a common medical term for thoughts about suicide, which may be as detailed as a formulated plan, without the suicidal act itself. Although most people who undergo suicidal ideation do not commit suicide, some go on to make suicide attempts...
and suicidal behavior" by about 80%, and of agitation and hostility by about 130%.
More infrequently, studies have been inconclusive. There is also evidence that higher rates of SSRI prescriptions are associated with lower rates of suicide in children, though since the evidence is correlation
Correlation
In statistics, dependence refers to any statistical relationship between two random variables or two sets of data. Correlation refers to any of a broad class of statistical relationships involving dependence....
al, the true nature of the relationship is unclear.
In 2004, the Medicines and Healthcare products Regulatory Agency
Medicines and Healthcare products Regulatory Agency
The Medicines and Healthcare products Regulatory Agency is the UK government agency which is responsible for ensuring that medicines and medical devices work and are acceptably safe....
(MHRA) in the United Kingdom
United Kingdom
The United Kingdom of Great Britain and Northern IrelandIn the United Kingdom and Dependencies, other languages have been officially recognised as legitimate autochthonous languages under the European Charter for Regional or Minority Languages...
judged fluoxetine
Fluoxetine
Fluoxetine is an antidepressant of the selective serotonin reuptake inhibitor class. It is manufactured and marketed by Eli Lilly and Company...
(Prozac) to be the only antidepressant that offered a favorable risk-benefit ratio
Risk-benefit analysis
Risk–benefit analysis is the comparison of the risk of a situation to its related benefits. Exposure to personal risk is recognized as a normal aspect of everyday life. We accept a certain level of risk in our lives as necessary to achieve certain benefits. In most of these risks we feel as though...
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
Sertraline
Sertraline hydrochloride is an antidepressant of the selective serotonin reuptake inhibitor class. It was introduced to the market by Pfizer in 1991. Sertraline is primarily used to treat major depression in adult outpatients as well as obsessive–compulsive, panic, and social anxiety disorders in...
(Zoloft) and fluvoxamine
Fluvoxamine
Fluvoxamine is an antidepressant which functions as a selective serotonin reuptake inhibitor . Fluvoxamine was first approved by the U.S. Food and Drug Administration in 1993 for the treatment of obsessive compulsive disorder . Fluvoxamine CR is approved to treat social anxiety disorder...
(Luvox), and only for the treatment of obsessive–compulsive disorder. Fluoxetine, despite having a favorable risk-benefit ratio for use with depression in adolescents and children, is not licensed for this use.
Adults
It is unclear whether or not SSRIs affect the risk of suicidal behavior for 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. Also among high-risk adult patients, antidepressant drug treatment does not seem related to suicide attempts and death.
- A 2005 review observed that suicide attempts are increased in those who use SSRIs as compared to placeboPlaceboA placebo is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient...
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” appear to have led to 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 suggests 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.
Suicide warnings
The FDA findings resulted in a black box warningBlack box warning
In the United States, a black box warning is a type of warning that appears on the package insert for prescription drugs that may cause serious adverse effects...
on SSRI and other antidepressant medications regarding the increased risk of suicidal behavior in patients younger than 24. Similar precautionary notice revisions were implemented by the Japanese Ministry of Health. In 2004 the Medicines and Healthcare products Regulatory Agency
Medicines and Healthcare products Regulatory Agency
The Medicines and Healthcare products Regulatory Agency is the UK government agency which is responsible for ensuring that medicines and medical devices work and are acceptably safe....
in the United Kingdom issued a warning about increases in 'insomnia, agitation, weight loss, headache, tremor, loss of appetite, self harm and suicidal thoughts' when the medications are used with children and adolescents.
The introduction of a warning regarding the association between SSRIs and suicide by the FDA in 2004 led to a dramatic decrease in prescriptions of these medications to young people. Originally, there were concerns that the decrease in prescriptions caused by the warnings could increase the number of teenage suicides in the US. However, the most recent data from the US National Center for Health Statistics put these concerns to rest. The suicide rates for persons younger than 25 has actually decreased between 2004 and 2007.
Aggression
A recent comparison of aggression and hostility occurring during treatment with fluoxetine to placebo in children and adolescents found that non-significantly less aggression and hostility occurred in the fluoxetine group than in the placebo group.Pregnancy and breastfeeding
SSRIs are not considered major teratogens. They do, however, cross the placenta and may thus affect the newborn. SertralineSertraline
Sertraline hydrochloride is an antidepressant of the selective serotonin reuptake inhibitor class. It was introduced to the market by Pfizer in 1991. Sertraline is primarily used to treat major depression in adult outpatients as well as obsessive–compulsive, panic, and social anxiety disorders in...
and paroxetine
Paroxetine
Paroxetine is an SSRI antidepressant. Marketing of the drug began in 1992 by the pharmaceutical company SmithKline Beecham, now GlaxoSmithKline...
, and SSRI as a group have been associated with congenital malformations
Congenital disorder
A congenital disorder, or congenital disease, is a condition existing at birth and often before birth, or that develops during the first month of life , regardless of causation...
, in particular, septal defects. Some evidence suggests that SSRIs are associated with neonatal complications such as neonatal abstinence syndrome (NAS) and persistent pulmonary hypertension
Pulmonary hypertension
In medicine, pulmonary hypertension is an increase in blood pressure in the pulmonary artery, pulmonary vein, or pulmonary capillaries, together known as the lung vasculature, leading to shortness of breath, dizziness, fainting, and other symptoms, all of which are exacerbated by exertion...
(PPHN).
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
Neonatal abstinence syndrome is a withdrawal syndromeWithdrawal
Withdrawal can refer to any sort of separation, but is most commonly used to describe the group of symptoms that occurs upon the abrupt discontinuation/separation or a decrease in dosage of the intake of medications, recreational drugs, and alcohol...
in newborn babies
Infant
A newborn or baby is the very young offspring of a human or other mammal. A newborn is an infant who is within hours, days, or up to a few weeks from birth. In medical contexts, newborn or neonate refers to an infant in the first 28 days after birth...
. It has been documented in SSRI treatment. By November 2003, a total of 93 cases of SSRI use associated with either neonatal convulsions or withdrawal syndrome had been reported. Subsequently, the authors of a Lancet
The Lancet
The Lancet is a weekly peer-reviewed general medical journal. It is one of the world's best known, oldest, and most respected general medical journals...
study concluded that doctors should avoid or cautiously manage the prescribing of these drugs to pregnant women with psychiatric disorders.
Permanent neuropsychological changes
Since the early 80's scientists have used a technique called neonatal clomipramine to produce animals used in depression research. If rats are given the tricyclic antidepressant clomipramineClomipramine
Clomipramine is a tricyclic antidepressant . It was developed in the 1960s by the Swiss drug manufacturer Geigy and has been in clinical use worldwide ever since.- Indications :...
when 8–21 days old, they develop behavioural changes in adulthood that resemble depression in humans. In 1997 Lundbeck found that treatment with the SSRI LU-10-134-C, which only differs from their product citalopram by two atoms could give similar results as clomipramine. Later it was found that neonatal citalopram and escitalopram makes persistent changes in the serotonergic transmission of the brain resulting in behavioral changes, which are reversed by treatment with antidepressants.
By treating normal and knockout mice
Knockout mouse
A knockout mouse is a genetically engineered mouse in which researchers have inactivated, or "knocked out," an existing gene by replacing it or disrupting it with an artificial piece of DNA...
lacking the serotonin transporter with fluoxetine scientists showed that normal emotional reactions in adulthood, like a short latency to escape foot shocks and inclination to explore new environments were dependent on active serotonin transporters during the neonatal period.
But when young mice were treated with the SNRI desimipramine they developed to normal adults, which suggests that serotonin and noradrenaline have different effects in the developing brain. For humans, the developmental stage sensitive to SSRI:s corresponds with the last trimester to the first years of life. A study showed that 4-year old children perinatally exposed to SSRIs behave normally. However, the young mice and rats also seem normal until they reach puberty and develop behavioural disturbances.
The mechanism is currently unknown, but it seems that early life overstimulation of the 5HT-1 receptor that regulates serotonin production results in low serotonin production after puberty.
Persistent pulmonary hypertension
Persistent pulmonary hypertensionPulmonary hypertension
In medicine, pulmonary hypertension is an increase in blood pressure in the pulmonary artery, pulmonary vein, or pulmonary capillaries, together known as the lung vasculature, leading to shortness of breath, dizziness, fainting, and other symptoms, all of which are exacerbated by exertion...
(PPHN) is a serious and life-threatening, but rare, lung condition that occurs soon after birth of the newborn. Newborn babies
Infant
A newborn or baby is the very young offspring of a human or other mammal. A newborn is an infant who is within hours, days, or up to a few weeks from birth. In medical contexts, newborn or neonate refers to an infant in the first 28 days after birth...
with PPHN have high pressure in their lung blood vessel
Blood vessel
The blood vessels are the part of the circulatory system that transports blood throughout the body. There are three major types of blood vessels: the arteries, which carry the blood away from the heart; the capillaries, which enable the actual exchange of water and chemicals between the blood and...
s 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
Health care
Health care is the diagnosis, treatment, and prevention of disease, illness, injury, and other physical and mental impairments in humans. Health care is delivered by practitioners in medicine, chiropractic, dentistry, nursing, pharmacy, allied health, and other care providers...
. One study has found that PPHN is six times more common in babies whose mothers take an SSRI antidepressant after the 20th week of the pregnancy compared to babies whose mothers do not take an antidepressant.
Bleeding tendencies
Many reports have been published incriminating SSRIs with increased bleeding tendencies. SSRIs are known to cause platelet dysfunction. SSRIs, fluoxetine and sertraline have also been found to increase gastric acid secretion in rats and so can be ulcerogenic particularly when combined with NSAIDs. Though the overall risk may be very small but case reports of life threatening bleeding have also been reported.Overdose
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
Therapeutic index
The therapeutic index is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes death or toxicity ....
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 syndrome
Serotonin syndrome is a potentially life-threatening adverse drug reaction that may occur following therapeutic drug use, inadvertent interactions between drugs, overdose of particular drugs, or the recreational use of certain drugs...
; serotonin toxicity is usually associated with very high overdoses or multiple drug ingestion. Other reported significant effects include coma
Coma
In medicine, a coma is a state of unconsciousness, lasting more than 6 hours in which a person cannot be awakened, fails to respond normally to painful stimuli, light or sound, lacks a normal sleep-wake cycle and does not initiate voluntary actions. A person in a state of coma is described as...
, seizure
Seizure
An epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...
s, and cardiac toxicity
Cardiotoxicity
Cardiotoxicity is the occurrence of heart electrophysiology dysfunction or/and muscle damage. The heart becomes weaker and is not as efficient in pumping and therefore circulating blood...
.
Treatment for SSRI overdose is mainly based on symptomatic and supportive care. Medical care may be required for agitation, maintenance of the airways, and treatment for serotonin syndrome. ECG monitoring is usually indicated to detect any cardiac abnormalities.
Contraindications and drug interaction
One major contraindication of SSRIs is the concomitant use of MAOIs (monoamine oxidase inhibitorMonoamine oxidase inhibitor
Monoamine oxidase inhibitors are a class of antidepressant drugs prescribed for the treatment of depression. They are particularly effective in treating atypical depression....
s). This is likely to cause severe serotonin syndrome/toxidrome
Serotonin syndrome
Serotonin syndrome is a potentially life-threatening adverse drug reaction that may occur following therapeutic drug use, inadvertent interactions between drugs, overdose of particular drugs, or the recreational use of certain drugs...
.
People taking SSRIs should also avoid taking pimozide
Pimozide
Pimozide is an antipsychotic drug of the diphenylbutylpiperidine class. It was discovered at Janssen Pharmaceutica in 1963. It has a high potency compared to chlorpromazine . On a weight basis it is even more potent than haloperidol. It also has special neurologic indications for Tourette syndrome...
(an antipsychotic
Antipsychotic
An antipsychotic is a tranquilizing psychiatric medication primarily used to manage psychosis , particularly in schizophrenia and bipolar disorder. A first generation of antipsychotics, known as typical antipsychotics, was discovered in the 1950s...
diphenylbutylpiperidine derivative). Tramadol
Tramadol
Tramadol hydrochloride is a centrally acting synthetic opioid analgesic used in treating moderate pain. The drug has a wide range of applications, including treatment for restless legs syndrome and fibromyalgia...
hydrochloride (or Ultram, Ultracet) can, in rare cases, produce seizure
Seizure
An epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...
s when taken in conjunction with an SSRI or tricyclic antidepressant
Tricyclic antidepressant
Tricyclic antidepressants are heterocyclic chemical compounds used primarily as antidepressants. The TCAs were first discovered in the early 1950s and were subsequently introduced later in the decade; they are named after their chemical structure, which contains three rings of atoms...
. Liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
impairment is another contraindication for medications of this type.
SSRIs may increase blood levels and risk of toxicities of certain medications:
- highly protein-bound medications like warfarinWarfarinWarfarin is an anticoagulant. It is most likely to be the drug popularly referred to as a "blood thinner," yet this is a misnomer, since it does not affect the thickness or viscosity of blood...
(coumadin) and digoxinDigoxinDigoxin INN , also known as digitalis, is a purified cardiac glycoside and extracted from the foxglove plant, Digitalis lanata. Its corresponding aglycone is digoxigenin, and its acetyl derivative is acetyldigoxin... - antiarrhythmic agentAntiarrhythmic agentAntiarrhythmic agents are a group of pharmaceuticals that are used to suppress abnormal rhythms of the heart , such as atrial fibrillation, atrial flutter, ventricular tachycardia, and ventricular fibrillation....
s like propafenonePropafenonePropafenone is a class Ic anti-arrhythmic medication, which treats illnesses associated with rapid heart beats such as atrial and ventricular arrhythmias.-Mechanism of action:...
(Rythmol) or flecainideFlecainideFlecainide acetate is a class Ic antiarrhythmic agent used to prevent and treat tachyarrhythmias . It is used to treat a variety of cardiac arrhythmias including paroxysmal atrial fibrillation , paroxysmal supraventricular tachycardia Flecainide acetate is a class Ic antiarrhythmic agent used to...
(Tambocor) - beta blockerBeta blockerBeta blockers or beta-adrenergic blocking agents, beta-adrenergic antagonists, beta-adrenoreceptor antagonists or beta antagonists, are a class of drugs used for various indications. They are particularly for the management of cardiac arrhythmias, cardioprotection after myocardial infarction ,...
s like metoprololMetoprololMetoprolol is a selective β1 receptor blocker used in treatment of several diseases of the cardiovascular system, especially hypertension. The active substance metoprolol is employed either as metoprolol succinate or metoprolol tartrate...
(Toprol xl) or propranolol (Inderal) - Tricyclic antidepressantTricyclic antidepressantTricyclic antidepressants are heterocyclic chemical compounds used primarily as antidepressants. The TCAs were first discovered in the early 1950s and were subsequently introduced later in the decade; they are named after their chemical structure, which contains three rings of atoms...
s like amitriptylineAmitriptylineAmitriptyline is a tricyclic antidepressant . It is the most widely used TCA and has at least equal efficacy against depression as the newer class of SSRIs...
(Elavil, Endep) etc. - triptans like sumatriptanSumatriptanSumatriptan is a triptan sulfa drug containing a sulfonamide group. It is used for the treatment of migraine headaches. Sumatriptan is produced and marketed by various drug manufacturers with many different trade names such as Sumatriptan, Imitrex, Imigran, Imigran recovery.-Approval and...
(Imitrex, Imigran) etc. - benzodiazepineBenzodiazepineA benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
s like alprazolamAlprazolamAlprazolam is a short-acting anxiolytic of the benzodiazepine class of psychoactive drugs. Alprazolam, like other benzodiazepines, binds to specific sites on the GABAA gamma-amino-butyric acid receptor...
(Xanax) or diazepamDiazepamDiazepam , first marketed as Valium by Hoffmann-La Roche is a benzodiazepine drug. Diazepam is also marketed in Australia as Antenex. It is commonly used for treating anxiety, insomnia, seizures including status epilepticus, muscle spasms , restless legs syndrome, alcohol withdrawal,...
(Valium) - carbamazepineCarbamazepineCarbamazepine is an anticonvulsant and mood-stabilizing drug used primarily in the treatment of epilepsy and bipolar disorder, as well as trigeminal neuralgia...
(Tegretol) - cisaprideCisaprideCisapride is a gastroprokinetic agent, a drug which increases motility in the upper gastrointestinal tract. It acts directly as a serotonin 5-HT4 receptor agonist and indirectly as a parasympathomimetic. Stimulation of the serotonin receptors increases acetylcholine release in the enteric nervous...
(Propulsid) - clozapineClozapineClozapine is an antipsychotic medication used in the treatment of schizophrenia, and is also used off-label in the treatment of bipolar disorder. Wyatt. R and Chew...
(Clozaril) - ciclosporinCiclosporinCiclosporin , cyclosporine , cyclosporin , or cyclosporin A is an immunosuppressant drug widely used in post-allogeneic organ transplant to reduce the activity of the immune system, and therefore the risk of organ rejection...
(Neoral) - haloperidolHaloperidolHaloperidol is a typical antipsychotic. It is in the butyrophenone class of antipsychotic medications and has pharmacological effects similar to the phenothiazines....
(Haldol) - phenytoinPhenytoinPhenytoin sodium is a commonly used antiepileptic. Phenytoin acts to suppress the abnormal brain activity seen in seizure by reducing electrical conductance among brain cells by stabilizing the inactive state of voltage-gated sodium channels...
(Dilantin) - pimozidePimozidePimozide is an antipsychotic drug of the diphenylbutylpiperidine class. It was discovered at Janssen Pharmaceutica in 1963. It has a high potency compared to chlorpromazine . On a weight basis it is even more potent than haloperidol. It also has special neurologic indications for Tourette syndrome...
(Orap) - theophyllineTheophyllineTheophylline, also known as dimethylxanthine, is a methylxanthine drug used in therapy for respiratory diseases such as COPD and asthma under a variety of brand names. Because of its numerous side-effects, the drug is now rarely administered for clinical use. As a member of the xanthine family, it...
(Theo-dur)
Certain drugs may increase toxicities of SSRIs:
- alcoholAlcoholIn chemistry, an alcohol is an organic compound in which the hydroxy functional group is bound to a carbon atom. In particular, this carbon center should be saturated, having single bonds to three other atoms....
and other CNS depressants - methylene blueMethylene blueMethylene blue is a heterocyclic aromatic chemical compound with the molecular formula C16H18N3SCl. It has many uses in a range of different fields, such as biology and chemistry. At room temperature it appears as a solid, odorless, dark green powder, that yields a blue solution when dissolved in...
dye - diureticDiureticA diuretic provides a means of forced diuresis which elevates the rate of urination. There are several categories of diuretics. All diuretics increase the excretion of water from bodies, although each class does so in a distinct way.- Medical uses :...
s (water pills) - MAOIs – possibly fatal serotonin syndrome/toxidromeSerotonin syndromeSerotonin syndrome is a potentially life-threatening adverse drug reaction that may occur following therapeutic drug use, inadvertent interactions between drugs, overdose of particular drugs, or the recreational use of certain drugs...
- sympathomimetic drugs like pseudoephedrinePseudoephedrinePseudoephedrine is a sympathomimetic drug of the phenethylamine and amphetamine chemical classes. It is used as a nasal/sinus decongestant and stimulant, or as a wakefulness-promoting agent....
(Sudafed) - lithiumLithiumLithium is a soft, silver-white metal that belongs to the alkali metal group of chemical elements. It is represented by the symbol Li, and it has the atomic number 3. Under standard conditions it is the lightest metal and the least dense solid element. Like all alkali metals, lithium is highly...
- sibutramineSibutramineSibutramine is an oral anorexiant. Until 2010 it was marketed and prescribed as an adjunct in the treatment of exogenous obesity along with diet and exercise...
(Meridia) - MDMA (ecstasy)
- zolpidemZolpidemZolpidem is a prescription medication used for the short-term treatment of insomnia, as well as some brain disorders. It is a short-acting nonbenzodiazepine hypnotic of the imidazopyridine class that potentiates gamma-aminobutyric acid , an inhibitory neurotransmitter, by binding to GABAA...
(ambien) - dextromethorphanDextromethorphanDextromethorphan is an antitussive drug. It is one of the active ingredients in many over-the-counter cold and cough medicines, such as Robitussin, NyQuil, Dimetapp, Vicks, Coricidin, Delsym, and others, including generic labels. Dextromethorphan has also found other uses in medicine, ranging...
(cough suppressant) – increased risk of serotonin syndrome/toxidromeSerotonin syndromeSerotonin syndrome is a potentially life-threatening adverse drug reaction that may occur following therapeutic drug use, inadvertent interactions between drugs, overdose of particular drugs, or the recreational use of certain drugs... - tramadolTramadolTramadol hydrochloride is a centrally acting synthetic opioid analgesic used in treating moderate pain. The drug has a wide range of applications, including treatment for restless legs syndrome and fibromyalgia...
(synergistic serotoninergic effect said to increase risk of seizure or serotonin syndrome/toxidromeSerotonin syndromeSerotonin syndrome is a potentially life-threatening adverse drug reaction that may occur following therapeutic drug use, inadvertent interactions between drugs, overdose of particular drugs, or the recreational use of certain drugs...
) - pethidine/meperidinePethidinePethidine or meperidine Pethidine (INN) or meperidine (USAN) Pethidine (INN) or meperidine (USAN) (commonly referred to as Demerol but also referred to as: isonipecaine; lidol; pethanol; piridosal; Algil; Alodan; Centralgin; Dispadol; Dolantin; Mialgin (in Indonesia); Petidin Dolargan (in Poland);...
– increased risk of serotonin syndrome/toxidromeSerotonin syndromeSerotonin syndrome is a potentially life-threatening adverse drug reaction that may occur following therapeutic drug use, inadvertent interactions between drugs, overdose of particular drugs, or the recreational use of certain drugs... - herbal Saint John's wort or yohimbe – increased risk of serotonin syndrome/toxidromeSerotonin syndromeSerotonin syndrome is a potentially life-threatening adverse drug reaction that may occur following therapeutic drug use, inadvertent interactions between drugs, overdose of particular drugs, or the recreational use of certain drugs...
Painkillers of the NSAIDs drug family may interfere and reduce efficiency of SSRIs :
- AspirinAspirinAspirin , also known as acetylsalicylic acid , is a salicylate drug, often used as an analgesic to relieve minor aches and pains, as an antipyretic to reduce fever, and as an anti-inflammatory medication. It was discovered by Arthur Eichengrun, a chemist with the German company Bayer...
- Ibuprofen (Advil,Nurofen)
- NaproxenNaproxenNaproxen sodium is a nonsteroidal anti-inflammatory drug commonly used for the reduction of pain, fever, inflammation and stiffness caused by conditions such as:...
(Aleve)
SSRIs also directly interfere with ligands of 5-HT receptors, like the psychedelic
Psychedelic
The term psychedelic is derived from the Greek words ψυχή and δηλοῦν , translating to "soul-manifesting". A psychedelic experience is characterized by the striking perception of aspects of one's mind previously unknown, or by the creative exuberance of the mind liberated from its ostensibly...
s and entactogens. SSRIs strongly attenuate the effects of tryptamine
Tryptamine
Tryptamine is a monoamine alkaloid found in plants, fungi, and animals. It is based around the indole ring structure, and is chemically related to the amino acid tryptophan, from which its name is derived...
psychedelics like psilocybin
Psilocybin
Psilocybin is a naturally occurring psychedelic prodrug, with mind-altering effects similar to those of LSD and mescaline, after it is converted to psilocin. The effects can include altered thinking processes, perceptual distortions, an altered sense of time, and spiritual experiences, as well as...
and LSD
LSD
Lysergic acid diethylamide, abbreviated LSD or LSD-25, also known as lysergide and colloquially as acid, is a semisynthetic psychedelic drug of the ergoline family, well known for its psychological effects which can include altered thinking processes, closed and open eye visuals, synaesthesia, an...
, and almost completely eliminate the serotonergic effects of phenethylamine
Phenethylamine
Phenylethylamine or phenethylamine is a natural monoamine alkaloid, trace amine, and also the name of a class of chemicals with many members well known for psychoactive drug and stimulant effects. Studies suggest that phenylethylamine functions as a neuromodulator or neurotransmitter in the...
psychedelics like mescaline
Mescaline
Mescaline or 3,4,5-trimethoxyphenethylamine is a naturally occurring psychedelic alkaloid of the phenethylamine class used mainly as an entheogen....
and MDMA. The exact mechanism that causes this interaction is still unclear. However, salvinorin A
Salvinorin A
Salvinorin A is the main active psychotropic molecule in Salvia divinorum, a Mexican plant which has a long history of use as an entheogen by indigenous Mazatec shamans...
(found in Salvia divinorum
Salvia divinorum
Salvia divinorum is a psychoactive plant which can induce dissociative effects and is a potent producer of "visions" and other hallucinatory experiences...
) has no actions at the 5-HT2A serotonin receptor, nor is it known to have affinity for any other sites to date.
Mechanism of action
SSRIs are believed to act by inhibiting the reuptake of serotoninSerotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
after being released in synapses. How much an individual will respond to this, however, also depends on genetics. In addition, several other mechanisms are suggested for the desired effect, e.g. neuroprotection and anti-inflammatory and immunomodulatory factors. Taken together, SSRI has several advantages compared with tricyclic antidepressant
Tricyclic antidepressant
Tricyclic antidepressants are heterocyclic chemical compounds used primarily as antidepressants. The TCAs were first discovered in the early 1950s and were subsequently introduced later in the decade; they are named after their chemical structure, which contains three rings of atoms...
s (TCA)s and 5-HT-prodrug
Prodrug
A prodrug is a pharmacological substance administered in an inactive form. Once administered, the prodrug is metabolised in vivo into an active metabolite, a process termed bioactivation. The rationale behind the use of a prodrug is generally for absorption, distribution, metabolism, and...
s. However, the latter might be required in addition to SSRIs in certain situations.
Basic understanding
In the brainBrain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
, messages are passed between two nerve cells
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
via a chemical synapse
Chemical synapse
Chemical synapses are specialized junctions through which neurons signal to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous system. They are crucial to the biological computations that underlie...
, a small gap between the cells. The (presynaptic) cell that sends the information releases neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
s (including serotonin) into that gap. The neurotransmitters are then recognized by receptor
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
s 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 transporter
Monoamine transporter
Monoamine transporters are protein structures that function as integral plasma membrane transporters to regulate concentrations of extracellular monoamine neurotransmitters. Three major classes of MATs are responsible for the reuptake of their associated amine neurotransmitters...
s into the sending (presynaptic) cell (a process called reuptake).
To stimulate the recipient cell, 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. The current model of SSRIs (the Monoamine Hypothesis) assumes that a lower homeostatic level of serotonin is primarily responsible for depression. While this holds in cases of major depression, minor to moderate cases are not as clear cut, and may in fact be caused by excess serotonin in specific areas of the brain.
Some current research points to more than just a single type of chemical signaling - the classic synapse model - involving serotonin. Astrocytes are "helper cells" in the brain that do not participate directly in chemical signaling, but play a part in homeostasis for many chemical levels in the brain. Recent research suggests that serotonin is one of the hormones regulated by astrocytes, and that astrocytes actually uptake, package, and resend serotonin in a way similar to neuronal axons, but do not have corresponding post-synaptic terminals, therefore appearing to function only to control the local levels of serotonin in the cerebrospinal fluid.
Still more research illustrates that the current model for the antidepressant activity of SSRIs may be misdirected, as a drug that works entirely opposite to SSRIs - Tianeptine
Tianeptine
Tianeptine was discovered by The French Society of Medical Research in the 1960s. Under the trade-names it is a drug used for treating major depressive episodes ....
, a selective serotonin reuptake enhancer - also exhibits antidepressant activity, especially in patients resistant to SSRI therapy. The effect of an SSRE in comparison to an SSRI requires that the nature of serotonin signaling in the areas of the brain related to mood and cognition needs further elucidation. If serotonin firing is regularly phasic (related to brain waves), or rapid and discrete, then SSRIs simply compress the signal potential at affected receptors (bringing down the maximum potential and bring up the minimum) by causing a constant leftover signal (serotonin left in the synaptic gap) coupled with weaker subsequent signals (due to the decrease in presynaptic serotonin available to send new signals). By this hypothetical model, SSREs increase the signal potential separation (min to max) at affected 5-HT sites by reducing the level of free cerebrospinal serotonin and increasing the amount uptaken into axons to send new signals.
Pharmacodynamics
SSRIs inhibit the reuptake of the neurotransmitter serotoninSerotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
(5-hydroxytryptamine or 5-HT) into the presynaptic cell, increasing levels of 5-HT within the synaptic cleft.
However, there is one counteracting effect: high serotonin levels will not only activate the postsynaptic receptors, but also flood presynaptic autoreceptor
Autoreceptor
An autoreceptor is a receptor located on presynaptic nerve cell membranes and serves as a part of a feedback loop in signal transduction. It is sensitive only to those neurotransmitters or hormones that are released by the neuron in whose membrane the autoreceptor sits.Canonically, a presynaptic...
s, which serve as a feedback sensor for the cell. Activation of the autoreceptors (by agonist
Agonist
An agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...
s like serotonin) triggers a throttling of serotonin production. The resulting serotonin deficiency persists for some time, as the transporter inhibition occurs downstream to the cause of the deficiency and therefore, is not able to counterbalance the serotonin deficiency. The body adapts gradually to this situation by lowering (downregulating
Downregulation and upregulation
Downregulation is the process by which a cell decreases the quantity of a cellular component, such as RNA or protein, in response to an external variable...
) the sensitivity of the autoreceptors.
Another adaptive process provoked by SSRIs is the downregulation of postsynaptic serotonin 5-HT2A receptors
5-HT2A receptor
The mammalian 5-HT2A receptor is a subtype of the 5-HT2 receptor that belongs to the serotonin receptor family and is a G protein-coupled receptor . This is the main excitatory receptor subtype among the GPCRs for serotonin , although 5-HT2A may also have an inhibitory effect on certain areas such...
. After the use of an SSRI, since there is more serotonin available, the response is to decrease the number of postsynaptic receptors over time and in the long run, this modifies the serotonin/receptor ratio. This downregulation of 5-HT2A occurs when the antidepressant effects of SSRIs become apparent. Also, deceased suicidal and otherwise depressed patients have had more 5-HT2A receptors than normal patients. These considerations suggest that 5-HT2A overactivity is involved in the pathogenesis of depression.
Most of the serotonin receptors on the surface of the cell are coupled to a G-protein
G protein-coupled receptor
G protein-coupled receptors , also known as seven-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptor, and G protein-linked receptors , comprise a large protein family of transmembrane receptors that sense molecules outside the cell and activate inside signal...
inside it. These proteins activate or inhibit second messengers, which in turn affect transcription factor
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
s. Transcription factors are proteins that fit to the beginning of a gene and tell the cell to start using it.
These (slowly proceeding) neurophysiological adaptations of the brain tissue are the reason why usually several weeks of continuous SSRI use is necessary for the antidepressant effect to become fully manifested, and why increased anxiety is a common side effect in the first few days or weeks of use.
Role in BDNF release
SSRIs act on signal pathways such as cAMP (Cyclic AMP) 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.Pharmacogenetics
Large bodies of research are devoted to using genetic markerGenetic marker
A genetic marker is a gene or DNA sequence with a known location on a chromosome that can be used to identify cells, individuals or species. It can be described as a variation that can be observed...
s to predict whether patients will respond to SSRIs or have side effects that will cause their discontinuation
Discontinuation
Discontinuation is the process of quitting a procedure, such as, the course of treatment with a drug or a consumer product line.*Discontinuation of a treatment is to stop taking a drug...
, although these tests are not yet ready for widespread clinical use. Single-nucleotide polymorphisms of the 5-HT(2A) gene correlated with paroxetine
Paroxetine
Paroxetine is an SSRI antidepressant. Marketing of the drug began in 1992 by the pharmaceutical company SmithKline Beecham, now GlaxoSmithKline...
discontinuation due to side effects in a group of elderly patients with major depression, but not mirtazapine
Mirtazapine
Mirtazapine is a tetracyclic antidepressant used primarily in the treatment of depression. It is also sometimes used as a hypnotic, antiemetic, and appetite stimulant, and for the treatment of anxiety, among other indications...
(a non-SSRI antidepressant) discontinuation.
Neuroprotection
Studies have suggested that SSRIs may promote the growth of new neural pathwayNeural pathway
A neural pathway, neural tract, or neural face, connects one part of the nervous system with another and usually consists of bundles of elongated, myelin-insulated neurons, known collectively as white matter...
s or neurogenesis
Neurogenesis
Neurogenesis is the process by which neurons are generated from neural stem and progenitor cells. Most active during pre-natal development, neurogenesis is responsible for populating the growing brain with neurons. Recently neurogenesis was shown to continue in several small parts of the brain of...
in rats. Also, SSRIs may protect against neurotoxicity caused by other compounds (for instance fenfluramine
Fenfluramine
Fenfluramine is a drug that was part of the Fen-Phen anti-obesity medication . Fenfluramine was introduced on the U.S. market in 1973. It is the racemic mixture of two enantiomers, dextrofenfluramine and levofenfluramine...
) as well as from depression itself. SSRIs have been found to induce programmed cell death in Burkitt lymphoma and the brain tumors neuroblastoma and glioma with minimal effect on normal tissue.
Anti-inflammatory and immunomodulation
Recent studies show pro-inflammatory cytokineCytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
processes take place during depression, mania
Mania
Mania, the presence of which is a criterion for certain psychiatric diagnoses, is a state of abnormally elevated or irritable mood, arousal, and/ or energy levels. In a sense, it is the opposite of depression...
and bipolar disorder
Bipolar disorder
Bipolar disorder or bipolar affective disorder, historically known as manic–depressive disorder, is a psychiatric diagnosis that describes a category of mood disorders defined by the presence of one or more episodes of abnormally elevated energy levels, cognition, and mood with or without one or...
, in addition to somatic
Somatic
The term somatic means 'of the body',, relating to the body. In medicine, somatic illness is bodily, not mental, illness. The term is often used in biology to refer to the cells of the body in contrast to the germ line cells which usually give rise to the gametes...
disease (such as autoimmune hypersensitivity
Hypersensitivity
Hypersensitivity refers to undesirable reactions produced by the normal immune system, including allergies and autoimmunity. These reactions may be damaging, uncomfortable, or occasionally fatal. Hypersensitivity reactions require a pre-sensitized state of the host. The four-group classification...
) and it is possible that symptoms manifest in these psychiatric illnesses are being attenuated by pharmacological effect of antidepressants on the immune system.
SSRIs have demonstrated immunomodulatory and anti-inflammatory effects against pro-inflammatory cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
processes, specifically on the regulation of Interferon-gamma
Interferon-gamma
Interferon-gamma is a dimerized soluble cytokine that is the only member of the type II class of interferons. This interferon was originally called macrophage-activating factor, a term now used to describe a larger family of proteins to which IFN-γ belongs...
(IFN-gamma) and Interleukin-10 (IL-10), as well as TNF-alpha and Interleukin-6 (IL-6). Antidepressants have also been shown to suppress TH1
T helper cell
T helper cells are a sub-group of lymphocytes, a type of white blood cell, that play an important role in the immune system, particularly in the adaptive immune system. These cells have no cytotoxic or phagocytic activity; they cannot kill infected host cells or pathogens. Rather, they help other...
upregulation.
Future serotonergic antidepressants may be made to specifically target the immune system by either blocking the actions of pro-inflammatory cytokines or increasing the production of anti-inflammatory cytokines.
SSRIs versus TCAs
SSRIs are described as 'selectiveFunctional Selectivity
Functional selectivity is the ligand-dependent selectivity for certain signal transduction pathways in one and the same receptor. This can be present when a receptor has several possible signal transduction pathways...
' 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 no significant difference in effectiveness between SSRIs and tricyclic antidepressant
Tricyclic antidepressant
Tricyclic antidepressants are heterocyclic chemical compounds used primarily as antidepressants. The TCAs were first discovered in the early 1950s and were subsequently introduced later in the decade; they are named after their chemical structure, which contains three rings of atoms...
s, which were the most commonly used class of antidepressants before the development of SSRIs. However, SSRIs have the important advantage that their toxic dose
Drug overdose
The term drug overdose describes the ingestion or application of a drug or other substance in quantities greater than are recommended or generally practiced...
is high, and, therefore, they are much more difficult to use as a means to commit suicide
Suicide
Suicide is the act of intentionally causing one's own death. Suicide is often committed out of despair or attributed to some underlying mental disorder, such as depression, bipolar disorder, schizophrenia, alcoholism, or drug abuse...
. Further, they have fewer and milder side effects
Adverse drug reaction
An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...
. Tricyclic antidepressant also have a higher risk of serious cardiovascular side effects, which SSRIs lack.
SSRIs versus 5-HT-Prodrugs
Serotonin cannot be administered directly because when ingested orally, it will not cross the blood-brain barrierBlood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...
, and therefore would have no effect on brain functions. Also, serotonin would activate every synapse it reaches, whereas SSRIs only enhance a signal that is already present, but too weak to come through. In addition, hope for breaching the blood-brain barrier for causes such as severe depression is underway. The selectivity of the membrane can be reduced for a drug by injecting it in a concentrated sugar solution. The high osmotic pressure of the sugar solution causes the endothelial cells of the capillaries to shrink, which opens gaps between their tight junctions and makes the barrier more permeable. As a result the drug can enter the brain tissue.
SSRIs together with 5-HT-Prodrugs
BiosyntheticBiosynthesis
Biosynthesis is an enzyme-catalyzed process in cells of living organisms by which substrates are converted to more complex products. The biosynthesis process often consists of several enzymatic steps in which the product of one step is used as substrate in the following step...
serotonin is made from tryptophan
Tryptophan
Tryptophan is one of the 20 standard amino acids, as well as an essential amino acid in the human diet. It is encoded in the standard genetic code as the codon UGG...
, an amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
. In 1989, the Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
made tryptophan available by prescription
Medical prescription
A prescription is a health-care program implemented by a physician or other medical practitioner in the form of instructions that govern the plan of care for an individual patient. Prescriptions may include orders to be performed by a patient, caretaker, nurse, pharmacist or other therapist....
only, in response to an outbreak of eosinophilia-myalgia syndrome
Eosinophilia-myalgia syndrome
Eosinophilia–myalgia syndrome is an incurable and sometimes fatal flu-like neurological condition that is believed to have been caused by ingestion of poorly produced L-tryptophan supplements...
caused by impure L-tryptophan supplements sold over-the-counter
Over-the-counter drug
Over-the-counter drugs are medicines that may be sold directly to a consumer without a prescription from a healthcare professional, as compared to prescription drugs, which may be sold only to consumers possessing a valid prescription...
. With current standards, L-tryptophan is again available over the counter in the US as well as supplement 5-HTP, which is a direct precursor to serotonin.
Criticism
In late 2004 media attention was given to a proposed link between SSRI use and juvenile suicideTeenage suicide
Teenage suicide in the United States remains comparatively high in the 15 to 24 age group with 4,000 suicides in this age range in 2004, making it the third leading cause of death for those aged 15 to 24...
. For this reason, the use of SSRIs in pediatric cases of depression is now recognized by the United States FDA as warranting a cautionary statement to the parents of children who may be prescribed SSRIs by a family doctor
General practitioner
A general practitioner is a medical practitioner who treats acute and chronic illnesses and provides preventive care and health education for all ages and both sexes. They have particular skills in treating people with multiple health issues and comorbidities...
. The FDA's currently required packaging insert for SSRIs includes a warning (known as a "black box warning"
Black box warning
In the United States, a black box warning is a type of warning that appears on the package insert for prescription drugs that may cause serious adverse effects...
) that a pooled analysis of placebo controlled trials
Randomized controlled trial
A randomized controlled trial is a type of scientific experiment - a form of clinical trial - most commonly used in testing the safety and efficacy or effectiveness of healthcare services or health technologies A randomized controlled trial (RCT) is a type of scientific experiment - a form of...
of 9 antidepressant drugs (including multiple SSRIs) resulted in a risk of suicidal behavior that was twice that of placebo
Placebo
A placebo is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient...
. At the same time, in adults SSRIs do not increase the risk of suicide.
Critics of SSRIs claim that the widely-disseminated television and print advertising of SSRIs promotes an inaccurate message, oversimplifying what these medications actually do and deceiving the public.
The criticism stems from questions about the validity of claims that SSRIs work by 'correcting' chemical imbalance
Chemical imbalance
Chemical imbalance is one hypothesis about the cause of mental illness. Other causes that are debated include psychological and social causes....
s. Without accurately measuring patients' neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
levels to allow for continuous monitoring during treatment, it is impossible to know if one is correctly targeting a deficient neurotransmitter (i.e. correcting an imbalance), reaching a desirable level, or even introducing too much of a particular neurotransmitter. Thus it has been argued that SSRIs can actually cause chemical imbalances and abnormal brain states, as evidenced by the fact that many report problems of sexual dysfunction, whose effects last long after the medication has been discontinued. Hence, it is purported that when a patient discontinues an SSRI, they may have a chemical imbalance due to the rapid cessation of the drug that causes the discontinuation syndrome.
One possible mechanism is by inhibition of dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
rgic neurotransmission.
Biopsychiatrists believe that, among other factors, the balance of neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
s in the brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
is a biological regulator of mental health
Mental health
Mental health describes either a level of cognitive or emotional well-being or an absence of a mental disorder. From perspectives of the discipline of positive psychology or holism mental health may include an individual's ability to enjoy life and procure a balance between life activities and...
. In this theory, emotions within a "normal" spectrum reflect a proper balance of neurochemicals, but abnormally extreme emotions, such as clinical depression
Clinical depression
Major depressive disorder is a mental disorder characterized by an all-encompassing low mood accompanied by low self-esteem, and by loss of interest or pleasure in normally enjoyable activities...
, reflect an imbalance. Psychiatrists claim that medications regulate neurotransmitters, and many if not most psychiatrists also claim they treat abnormal personalities by removing a neurochemical excess or replenishing a deficit. On the other hand, Elliot Valenstein
Elliot Valenstein
Elliot S. Valenstein, PhD, is a professor emeritus of psychology and neuroscience at the University of Michigan. His theories challenge the conventional assumption that mental illness is biochemical, rejecting the 'chemical imbalance' theories used by drug companies in marketing their products,...
, a psychologist and neuroscientist, claims that the broad biochemical assertions and assumptions of mainstream psychiatry are not supported by evidence.
One controversial critic of antidepressants, Peter Breggin
Peter Breggin
Peter Roger Breggin is an American psychiatrist and critic of biological psychiatry and psychiatric medication. In his books, he advocates replacing psychiatry's use of drugs and electroconvulsive therapy with humanistic approaches, such as psychotherapy, education, and broader human...
, a physician who opposes the overuse of prescription medications to treat patients for mental health issues, predicted iatrogenic
Iatrogenesis
Iatrogenesis, or an iatrogenic artifact is an inadvertent adverse effect or complication resulting from medical treatment or advice, including that of psychologists, therapists, pharmacists, nurses, physicians and dentists...
issues that SSRIs incur on a significant percentage of patients. Another prominent SSRI critic is David Healy
David Healy (psychiatrist)
David Healy is an Irish psychiatrist who is currently a professor in Psychological Medicine at Cardiff University School of Medicine, Wales. He is also the director of North Wales School of Psychological Medicine. He became the centre of controversy concerning the influence of the pharmaceutical...
.
A widely-reported meta-analysis combined 35 clinical trials submitted to the U.S. Food and Drug Administration (FDA) before licensing of four newer antidepressants (including the SSRIs paroxetine
Paroxetine
Paroxetine is an SSRI antidepressant. Marketing of the drug began in 1992 by the pharmaceutical company SmithKline Beecham, now GlaxoSmithKline...
and fluoxetine
Fluoxetine
Fluoxetine is an antidepressant of the selective serotonin reuptake inhibitor class. It is manufactured and marketed by Eli Lilly and Company...
, and two non-SSRI antidepressants nefazodone
Nefazodone
Nefazodone is an antidepressant marketed by Bristol-Myers Squibb. Its sale was discontinued in 2003 in some countries due to the rare incidence of hepatotoxicity , which could lead to the need for a liver transplant, or even death. The incidence of severe liver damage is approximately 1 in every...
and venlafaxine
Venlafaxine
Venlafaxine is an antidepressant of the serotonin-norepinephrine reuptake inhibitor class. First introduced by Wyeth in 1993, now marketed by Pfizer, it is licensed for the treatment of major depressive disorder , as a treatment for generalized anxiety disorder, and comorbid indications in...
). The authors found that although the antidepressants were statistically superior to placebo
Placebo
A placebo is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient...
they did not exceed the NICE
NICE
NICE may refer to:* National Independent Cadres and Elites in Iraq* National Institute for Coordinated Experiments, a fictional organisation in C.S...
criteria for a 'clinically significant' effect. For more detail, see the section "Efficacy".
A study in The New England Journal of Medicine on a possible publication bias
Publication bias
Publication bias is the tendency of researchers, editors, and pharmaceutical companies to handle the reporting of experimental results that are positive differently from results that are negative or inconclusive, leading to bias in the overall published literature...
regarding the efficacy of SSRI medications in the treatment of depression suggests that their effectiveness and risk-benefit ratios may be greatly exaggerated. Of 74 studies registered with the United States FDA
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
, 37 with positive results were published in academic journal
Academic journal
An academic journal is a peer-reviewed periodical in which scholarship relating to a particular academic discipline is published. Academic journals serve as forums for the introduction and presentation for scrutiny of new research, and the critique of existing research...
s, while 22 studies with negative results were not published and 11 with negative results were published in a way that conveyed a positive outcome (one positive study was not published and three negative studies were published with results that were portrayed as negative). Overall, 94% of studies actually published were positive outcomes; when published and unpublished studies were included for analysis, the percentage of positive outcomes was 51%.
Although controversial, the existence of an SSRI-related withdrawal syndrome mimicking depression may inflate the therapeutic effect size reported in long-term (more than 6 months) placebo controlled trials of SSRI’s, due to a reliance on randomized discontinuation designs. Discontinuation trials are a variant of the classic 2-arm placebo controlled randomized controlled trials used in shorter placebo controlled studies of SSRI’s.
Lawsuits
Hundreds of lawsuits have been filed against drug manufacturers seeking compensation for harm attributed to the use of SSRIs. Suits based on product liabilityProduct liability
Product liability is the area of law in which manufacturers, distributors, suppliers, retailers, and others who make products available to the public are held responsible for the injuries those products cause...
, for example, often allege failure to adequately warn users of potential side effects. Manufacturers have defended many suits on the merits and settled many others. In 2005, the U.S. FDA asked manufacturers to include black box warning
Black box warning
In the United States, a black box warning is a type of warning that appears on the package insert for prescription drugs that may cause serious adverse effects...
s on antidepressant drug packaging. The inclusion of the black box warning may have led to a decrease in prescriptions of SSRIs and an increase in suicide.
See also
- Dopamine reuptake inhibitorDopamine reuptake inhibitorA dopamine reuptake inhibitor is a type of drug that acts as a reuptake inhibitor for the neurotransmitter dopamine by blocking the action of the dopamine transporter...
(DRI) - Norepinephrine reuptake inhibitorNorepinephrine reuptake inhibitorA norepinephrine reuptake inhibitor or adrenergic reuptake inhibitor , is a type of drug which acts as a reuptake inhibitor for the neurotransmitters norepinephrine and epinephrine by blocking the action of the norepinephrine transporter...
(NRI) - Norepinephrine-dopamine reuptake inhibitorNorepinephrine-dopamine reuptake inhibitorA norepinephrine-dopamine reuptake inhibitor is a drug which acts as a reuptake inhibitor for the neurotransmitters norepinephrine and dopamine by blocking the action of the norepinephrine transporter and the dopamine transporter , respectively...
(NDRI) - Reuptake inhibitorReuptake inhibitorA reuptake inhibitor , also known as a transporter blocker, is a drug that inhibits the plasmalemmal transporter-mediated reuptake of a neurotransmitter from the synapse into the pre-synaptic neuron, leading to an increase in the extracellular concentrations of the neurotransmitter and therefore an...
- Serotonin reuptake inhibitor (SRI)
- Serotonin-norepinephrine reuptake inhibitorSerotonin-norepinephrine reuptake inhibitorSerotonin–norepinephrine reuptake inhibitors are a class of antidepressant drugs used in the treatment of major depression and other mood disorders...
(SNRI) - Serotonin-norepinephrine-dopamine reuptake inhibitor (SNDRI)
External links
- "black box" warning for SSRIs at the U.S. Food and Drug Administration
- FDA list of SSRIs receiving the black box warningBlack box warningIn the United States, a black box warning is a type of warning that appears on the package insert for prescription drugs that may cause serious adverse effects...
at FDA - PROZAC Product/Prescribing Information at Eli Lilly and CompanyEli Lilly and CompanyEli Lilly and Company is a global pharmaceutical company. Eli Lilly's global headquarters is located in Indianapolis, Indiana, in the United States...
- Barry Yeoman Putting Science in the Dock, The Nation at barryyeoman.com