A class of compounds typically used as antidepressants in the treatment of depression, anxiety disorders, and some personality disorders.
SSRIs form a subclass of serotonin uptake inhibitors, which includes other non-selective inhibitors:
Serotonin-norepinephrine reuptake inhibitors
serotonin-norepinephrine-dopamine reuptake inhibitors
selective serotonin reuptake enhancers are also serotonergic antidepressants.
SSRIs are believed to act by inhibiting the reuptake of serotonin after being released in synapses.
SSRIs are selective as they affect only the reuptake pumps responsible for serotonin, as opposed to earlier antidepressants, which affect other monoamine neurotransmitters as well.
SSRIs 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.
SSRIs having weak affinity for the noradrenaline and dopamine transporter.
Messages are passed in the brain between two nerve cells via a chemical synapse.
The presynaptic cell sending the information releases neurotransmitters into the synaptic gap.
Serotonin is among the neurotransmitters released.
The post synaptic receptors on the surface of postsynaptic cells recognize the neurotransmitters, which in turn relay the signals.
During synaptic transmission, about 10% of the neurotransmitters are lost.
The other 90% of neurotransmitters are released from the receptors and taken up again by monoamine transporters into the sending presynaptic cell, a process called reuptake.
SSRIs inhibit the reuptake of serotonin, and the serotonin stays in the synaptic gap longer than it normally would, and may repeatedly stimulate the receptors of the recipient cell.
It is assume that a lower level of serotonin is primarily responsible for major depression.
In cases of minor to moderate cases the effect is not as clear cut, and may in fact be caused by excess serotonin in specific areas of the brain.
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.
SSRIs inhibit the reuptake of the neurotransmitter serotonin into the presynaptic cell, increasing levels of 5-HT within the synaptic cleft.
High serotonin levels activate the postsynaptic receptors, but also flood presynaptic autoreceptors, which serve as a feedback sensor for the cell.
They down regulate postsynaptic serotonin 5-HTP2A receptors.
SSRIs make more serotonin available for use, and decrease the number of postsynaptic receptors over time and in the long run, this modifies the serotonin/receptor ratio.
These proteins activate or inhibit second messengers, which in turn affect transcription factors that allow neurophysiological adaptations of the brain that takes several weeks of continuous SSRI use is necessary for the antidepressant effect to become fully manifested,
There is not a substantial differences in efficacy among the various second generation antidepressants (SSRIs and SNRIs).
Anxiety is a common side effect in the first few days or weeks of use.
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.
Brain Derived Neurotrophic Factor enhances the growth and survival of cortical neurons and synapses
Deceased suicidal and otherwise depressed patients have had more 5-HT2A receptors than normal patients, suggesting that 5-HT2A overactivity is involved in the pathogenesis of depression.
Most serotonin receptors on the surface of the cell are couple to a G-protein inside it.
Frequently prescribed for anxiety disorders, such as social anxiety, panic disorders, obsessive–compulsive disorder,eating disorders, chronic pain and occasionally, for posttraumatic stress disorder.
Meta analyses of randomized, controlled clinical trials found a statistically significant effect of SSRIs on dependence, neurological deficit, depression, and anxiety.
Generally side effects are present during the first 1–4 weeks.
Usually the treatment is begun with a small dose that can subsequently be adjusted based on tolerance.
Mania or hypomania is a possible side effect, and patients with bipolar disorder are at a much higher risk.
Can cause sexual dysfunction such as anorgasmia, erectile dysfunction, and diminished libido.
Sexual side effects tend to occur later in treatment.
Sexual difficulties are found to be present in between 17% and 41% of patients, due to release of extracellular concentrations of serotonin in the brain decreasing dopamine and norepinephrine leading to erectile and/or sexual dysfunction.
Usually takes 6–8 weeks for the drug to reach its full potential.
The efficacy of different SSRI antidepressants is similar.
In mild and moderate depression, the effect of SSRIs is small or none compared to placebo.
In very severe depression the effect of SSRIs ranges between relatively small and substantial.
SSRIs are recommended over tricyclics due to their superior tolerability.
SSRIs are recommended for the second line treatment of adult obsessive compulsive disorder.
Efficacious in the treatment of OCD
In children, these agents are considered as a second line therapy in those with moderate-to-severe impairment.
They are also frequently used to treat depersonalization disorder.
Recommended as first-line treatment of severe depression and for the treatment of mild-to-moderate depression that persists after conservative measures.
Recommendation against routine use in patients with chronic health problems and mild depression.
Use has no advantage over placebo in the treatment of short term mild depression.
Benefits in the treatment of dysthymia and other forms of chronic mild depression.
In mild and moderate depression, the effect of SSRIs is small or none compared to placebo.
In very severe depression the effect varies between small and substantial.
Recommended over tricyclics due to their superior tolerability.
There is no significant difference in effectiveness between SSRIs and tricyclic antidepressants, however, SSRIs have the important advantage that their toxic dose is high.
It is more difficult to use SSRIs as a means to commit suicide, and have fewer and milder side effects.
Tricyclic antidepressant also have a higher risk of serious cardiovascular side effects, which SSRIs lack.
SSRIs are recommended for the treatment of generalized anxiety disorder (GAD) that has failed to respond to conservative measures.
GAD is a common disorder associated with excessive worry about multiple events and issues.
General anxiety disorder patients have difficulty controlling worrisome thoughts that persists for at least 6 months.
Antidepressants provide a modest-to-moderate reduction in anxiety in GAD.
No substantial differences in efficacy among the various second generation antidepressants (SSRIs and SNRIs).
SSRIs 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.
SSRI additional mechanisms neuroprotection and anti-inflammatory and immunomodulatory factors.
Anti-depressants are recommended in the treatment of bulimia nervosa.
Recommended as an alternative or additional first step to self-help programs in the treatment of bulimia nervosa.
Long term efficacy in depression is poorly characterized.
They provide short term reductions in binge eating behavior, but have not been associated with significant weight loss.
Anorexia nervosa management mostly negative with SSIRs.
Pro-inflammatory cytokine processes take place during depression, mania and bipolar disorder, and autoimmune hypersensitivity.
SSRIs have demonstrated immunomodulatory and anti-inflammatory effects against pro-inflammatory cytokine processes.
SSRIs are pref2242ed over other anti-depressants due to their acceptability, tolerability, and superior reduction of symptoms in short term trials.
Cardiovascular side effects are very rare,with a reported incidence of less than 0.0003 percent.
SSRIs inhibit cardiac and vascular sodium, calcium and potassium channels and prolong QT intervals.
Concerns about cardiac problems have led to a reduction in the recommended maximum dose of citalopram and escitalopram.
Similar recommendations apply to binge eating disorders.
Studies suggest mostly negative results for the use of SSRI’s in the treatment of anorexia nervosa.
SSRIs confer no advantage regarding weight gain, but that they may be used for the treatment of co-existing depressive, anxiety, or obsessive-compulsive disorders.
SSRIs having weak affinity for the noradrenaline and dopamine transporter.
They are the most widely prescribed antidepressants.
The main indication is major depressive disorder.
The individuals response depends on genetics.
First line treatment for depression in elderly because of safety and low risk of complications with overdose.
It is common among the elderly not to present classical depressive symptoms.
Treatment is further complicated in that the elderly are often simultaneously treated with a number of other drugs, and often have comorbid diseases.
Studies of SSRI-drugs have shown lesser and often inadequate effect among the elderly, while other drugs with more clear effects have adverse effects which can be especially difficult to handle among the elderly.
In a meta-analysis combined 35 clinical trials submitted to the U.S. Food and Drug Administration (FDA), antidepressants were statistically superior to placebo they did not exceed criteria for a clinically significant effect.
In the treatment of depression indicating the effectiveness and risk-benefit ratios may be greatly exaggerated.
SSRIs appear safer in overdose compared with traditional antidepressants, such as the tricyclic antidepressants.
Deaths have been reported following massive single ingestions, although this is exceedingly uncommon when compared to the tricyclic antidepressants.
Most commonly severe effect following SSRI overdose is serotonin syndrome, and associated coma, seizures, and cardiac toxicity.
Serotonin toxicity is usually associated with very high overdoses or multiple drug ingestion.
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.
Concomitant use of MAOIs is a major contraindication, likely to cause severe serotonin syndrome.
Tramadol hydrochloride can, in rare cases, produce seizures when taken in conjunction with an SSRI
People taking SSRIs should also avoid taking pimozide?
Liver impairment is another contraindication for medications of this type.
Do not have analgesic effects beyond their antidepressant activity.
Most common antidepressants used in women of child bearing age and not associated with increased risk of congenital malformations in children exposed during the first trimester, except for paroxetine.
Not associated with maternal use during pregnancy and autism spectrum disorder in offspring (Hviid A et al).
SSRI use during pregnancy is associated with an increased rate of miscarriages, birth defects, persistent pulmonary hypertension of the newborn, newborn behavioral syndrome, and possibly long term behavioral problems.
Persistent pulmonary hypertension 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.
The risk of spontaneous abortion is increased about 1.7 fold.
Use may be associated with autism.
Neonatal abstinence syndrome has been documented in SSRI treatment.
Some SSRIs are considered safe for breastfeeding.
Slows fetal growth.
Commonly prescribed SSRIs include:
Fluoxetine (Prozac)
Sertraline (Zoloft)
Paroxetine (Paxil)
Escitalopram (Lexapro)
Fluvoxamine (Luvox)
Citalopram (Celexa)
Vilazodone hydrochloride (Viibryd)
Among the most commonly prescribed antidepressant drugs for post stroke depression.
May benefit motor recovery in patients with stroke.
Used in the treatment of stroke patients, including those with and without symptoms of depression, but controlled clinical trials find a statistically significant effect of SSRIs on dependence, neurological deficit, depression, and anxiety, but no statistically significant effect on death, motor deficits, or cognition.
Considered convulsants, particular in patients with high daily dose, yet they are potential anticonvulsants.
Usually treatment is begun with a small dose, and after that the dose can be adjusted.
Mania or hypomania is a possible side effect, patients with some type of bipolar disorder are at a much higher risk.
SSRI-induced mania in patients previously diagnosed with unipolar depression can trigger a bipolar episode.
SSRIs have some dependence producing effects, most notably a withdrawal syndrome.
SSRIs have little abuse potential, but discontinuation can produce disturbing withdrawal symptoms that may be indistinguishable from a reoccurrence of the original illness.
Liver impairment is a contraindication for SSRI medications.
SSRIs may increase blood levels and of toxicities of certain medications:
highly protein-bound medications- warfarin, digoxin and flecainide
beta blockers
Tricyclic antidepressants
triptans
benzodiazepines
carbamazepine
clozapine
cyclosporin
haloperidol
phenytoin
pimozide
theophylline
Drugs may increase toxicities of SSRIs:
alcohol and other CNS depressants
methylene blue dye
diuretics
MAOIs
lithium
sibutramine
zolpidem
dextromethorphan associated with increased risk of serotonin syndrome/toxidrome.
tramadol-increases risk of seizure or serotonin syndrome/toxidrome
meperidine-increases risk of serotonin syndrome/toxidrome
herbal Saint John’s wort
Painkillers of the NSAIDs drug family may interfere and reduce efficiency of SSRIs
Aspirin
Ibuprofen
Naproxen
Drugs in this class include:
citalopram (Celexa)
dapoxetine (Priligy)
escitalopram (Lexapro)
fluoxetine (Prozac)
paroxetine (Paxil)
sertraline (Zoloft)
fluvoxamine(Luvox)
SSRIs have little abuse potential, but discontinuation can produce withdrawal symptoms that may be indistinguishable from a reoccurrence of the original illness.
When discontinuing an SSRI proper tapered reduction should take place.
Can be associated with various types of sexual dysfunction such as anorgasmia, erectile dysfunction, and diminished libido.
Sexual difficulties, and found that they are present in between 17% and 41% of patients
The release of extracellular concentrations of serotonin in the brain decreases dopamine and norepinephrine leading to erectile and/or sexual dysfunction.
The effect of SSRIs to slow down sexual stimulation may be used as treatment for premature ejaculation.
Almost all SSRIs are known to cause one or more of these symptoms:
nausea/vomiting
drowsiness or somnolence
headache
bruxism
extremely vivid or strange dreams
dizziness
mydriasis
changes in appetite
insomnia and/or changes in sleep
diarrhea
weight loss/gain
increased risk of bone fractures
changes in sexual behaviour
increased feelings of depression and anxiety
Provocation of panic attacks
mania
tremors
autonomic dysfunction including orthostatic hypotension, increased or reduced sweating
akathisia
suicidal ideation
photosensitivity
paresthesia
cognitive disorders
Syndrome of inappropriate antidiuretic hormone hypersecretion
Many side effects disappear when the antidepressant effects begin.
Most common adverse events are sexual, occurring in 17% of patients.
Continuous daily treatment is required to delay ejaculation significantly.
General side effects are mostly present during the first 1–4 weeks..
It often takes 6–8 weeks for the drug to begin reaching its full potential and the slow onset is considered a downside to treatment with SSRIs.
The two most dangerous adverse events associated with the use are increased risk of upper G.I. tract bleeding and hyponatremia.
SSRIs increase the risk of GI bleeding, post operative bleeding, and intracranial bleeding.
SSRIs are known to cause platelet dysfunction.
Medications are not recommended in children with mild disease.
There is also insufficient evidence to determine effectiveness of treatment in those with depression complicated by dementia.
SSRIs can cause or worsen insomnia.
SSRIs are not useful for preventing tension headaches or migraines.
Patients taking an SSRI have a 3-4 fold increase risk of having an upper G.I. bleed.
A patient taking a NSAID with a SSRI have a relative risk of an upper G.I. bleed greater than six.
Studies have found that SSRI use is related to a higher risk of suicidal behavior in children and adolescents.
Clinical trials on children with major depressive disorder found statistically significant increases of the risks of possible suicidal ideation and suicidal behavior by about 80%, and of agitation and hostility by about 130%.
Widespread use has led to highly significant decline in suicide rates in most countries with traditionally high baseline suicide rates.
The decline is particularly striking for women.
Controlled trials suggests that SSRIs increase suicide ideation compared with placebo.
A meta-analysis by the FDA 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.
The use of SSRIs in pediatric cases of depression is now recognized, resulting in a risk of suicidal behavior that was twice that of placebo.
In adults SSRIs do not increase the risk of suicide.