Serotonin-norepinephrine reuptake inhibitor

Serotonin–norepinephrine reuptake inhibitors (SNRIs) are a class of 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;...

drug

Drug

A drug, broadly speaking, is any substance that, when absorbed into the body of a living organism, alters normal bodily function. There is no single, precise definition, as there are different meanings in drug control law, government regulations, medicine, and colloquial usage.In pharmacology, a...

s used in the treatment of major depression and other mood disorder

Mood disorder

Mood disorder is the term designating a group of diagnoses in the Diagnostic and Statistical Manual of Mental Disorders classification system where a disturbance in the person's mood is hypothesized to be the main underlying feature...

s. They are sometimes also used to treat 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, obsessive-compulsive disorder

Obsessive-compulsive disorder

Obsessive–compulsive disorder is an anxiety disorder characterized by intrusive thoughts that produce uneasiness, apprehension, fear, or worry, by repetitive behaviors aimed at reducing the associated anxiety, or by a combination of such obsessions and compulsions...

(OCD), attention deficit hyperactivity disorder (ADHD), chronic neuropathic pain

Neuropathic pain

Neuropathic pain results from lesions or diseases affecting the somatosensory system. It may be associated with abnormal sensations called dysesthesia, which occur spontaneously and allodynia that occurs in response to external stimuli. Neuropathic pain may have continuous and/or episodic ...

, fibromyalgia syndrome (FMS), and for the relief of menopausal

Menopause

Menopause is a term used to describe the permanent cessation of the primary functions of the human ovaries: the ripening and release of ova and the release of hormones that cause both the creation of the uterine lining and the subsequent shedding of the uterine lining...

symptoms.

SNRIs act upon and increase the levels of two 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,...

that are known to play an important part in mood, 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...

and norepinephrine

Norepinephrine

Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...

. This can be contrasted with the more widely-used selective serotonin reuptake inhibitor

Selective serotonin reuptake inhibitor

Selective serotonin re-uptake inhibitors or serotonin-specific reuptake inhibitor are a class of compounds typically used as antidepressants in the treatment of depression, anxiety disorders, and some personality disorders. The efficacy of SSRIs is disputed...

s (SSRIs) which only act on serotonin.

Overview of SNRIs

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...

(Effexor) – The first and most commonly used SNRI. It was introduced by Wyeth
Wyeth
Wyeth, formerly one of the companies owned by American Home Products Corporation , was a pharmaceutical company. The company was based in Madison, New Jersey, USA...

in 1994. The reuptake effects of venlafaxine are dose dependent. At low doses (<150 mg/day) it acts only on serotonergic transmission. At moderate doses (>150 mg/day) it acts on serotonergic and noradrenergic systems, whereas at high doses (>300 mg/day) it also affects dopaminergic neurotransmission.

Desvenlafaxine
Desvenlafaxine
Desvenlafaxine , also known as O-desmethylvenlafaxine, is an antidepressant of the serotonin-norepinephrine reuptake inhibitor class developed and marketed by Wyeth . Desvenlafaxine is a synthetic form of the major active metabolite of venlafaxine...

(Pristiq) – The active metabolite of venlafaxine. It is believed to work in a similar manner, though some evidence suggests lower response rates compared to venlafaxine and duloxetine. It was introduced by Wyeth in May 2008.

Duloxetine
Duloxetine
Duloxetine is a serotonin-norepinephrine reuptake inhibitor manufactured and marketed by Eli Lilly. It is effective for major depressive disorder and has been shown to be as effective as venlafaxine for generalized anxiety disorder...

(Cymbalta, Yentreve) – By Eli Lilly and Company, has been approved for the treatment of depression and neuropathic pain
Neuropathic pain
Neuropathic pain results from lesions or diseases affecting the somatosensory system. It may be associated with abnormal sensations called dysesthesia, which occur spontaneously and allodynia that occurs in response to external stimuli. Neuropathic pain may have continuous and/or episodic ...

in August 2004. Duloxetine is contraindicated in patients with heavy alcohol use or chronic liver disease, as duloxetine can increase the levels of certain liver enzymes which can lead to acute hepatitis
Hepatitis
Hepatitis is a medical condition defined by the inflammation of the liver and characterized by the presence of inflammatory cells in the tissue of the organ. The name is from the Greek hepar , the root being hepat- , meaning liver, and suffix -itis, meaning "inflammation"...

or other diseases in certain at risk patients. Currently, the risk of liver damage appears only to be for patients already at risk, unlike the antidepressant 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...

which, though rare, can spontaneously cause liver failure in healthy patients. Duloxetine is also approved for Major Depressive Disorder (MDD), Generalized Anxiety Disorder (GAD), chronic musculoskeletal pain, including chronic osteoarthritis
Osteoarthritis
Osteoarthritis also known as degenerative arthritis or degenerative joint disease, is a group of mechanical abnormalities involving degradation of joints, including articular cartilage and subchondral bone. Symptoms may include joint pain, tenderness, stiffness, locking, and sometimes an effusion...

pain and chronic low back pain
Low back pain
Low back pain or lumbago is a common musculoskeletal disorder affecting 80% of people at some point in their lives. In the United States it is the most common cause of job-related disability, a leading contributor to missed work, and the second most common neurological ailment — only headache is...

(as of October, 2010), and is one of the only three medicines approved by the FDA for Fibromyalgia
Fibromyalgia
Fibromyalgia is a medical disorder characterized by chronic widespread pain and allodynia, a heightened and painful response to pressure. It is an example of a diagnosis of exclusion...

http://www.cymbalta.com/fibromyalgia.jsp?WT.seg_1=Fibro&DCSext.ag=Fibro&WT.mc_id=CymFibA39490001&WT.srch=1.

Milnacipran
Milnacipran
Milnacipran is a serotonin–norepinephrine reuptake inhibitor used in the clinical treatment of fibromyalgia...

(Dalcipran, Ixel, Savella) – Shown to be significantly effective in the treatment of depression and fibromyalgia. 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...

(FDA) approved milnacipran for treatment of fibromyalgia in the United States of America in January 2009, however it is currently not approved for depression in that country. Milnacipran has been commercially available in Europe and Asia for several years.

Levomilnacipran
Levomilnacipran
Levomilnacipran is an antidepressant currently under development by Forest Laboratories for the treatment of depression in the United States and Canada. As of 2009 it is in phase III clinical trials...

(F2695) – The levo- isomer of milnacipran. Under development for the treatment of depression in the United States and Canada.

Sibutramine
Sibutramine
Sibutramine 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, Reductil) – An SNRI, which, instead of being developed for the treatment of depression, was widely marketed as an appetite suppressant for weight loss
Weight loss
Weight 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...

purposes.

Bicifadine
Bicifadine
Bicifadine is a serotonin-norepinephrine reuptake inhibitor developed by DOV Pharmaceutical. It has been developed as an analgesic and is currently under development for the treatment of various pain conditions...

(DOV-220,075) – By DOV Pharmaceutical, potently inhibits the reuptake of serotonin and norepinephrine (and dopamine to a lesser extent), but rather than being developed for the already crowded antidepressant market, it is being researched as a non-opioid, non-NSAID analgesic
Analgesic
An analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos ....

.

SEP-227162
SEP-227162
SEP-227,162 is an antidepressant being developed by Sepracor which is currently in clinical trials. It acts as a serotonin-norepinephrine reuptake inhibitor. As of 1st July 2009, the compound has not shown sufficient efficacy, and its future development is unknown.- References :...

– An SNRI under development by Sepracor for the treatment of depression.

Edivoxetine (LY 2216684) – An SNRI under development by Eli Lilly for the treatment of depression.

Pharmacology

SNRIs work 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...

the 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....

of the neurotransmitters serotonin and norepinephrine. This results in an increase in 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...

concentrations of serotonin and norepinephrine and therefore an increase in neurotransmission

Neurotransmission

Neurotransmission , also called synaptic transmission, is the process by which signaling molecules called neurotransmitters are released by a neuron , and bind to and activate the receptors of another neuron...

.
Recent evidence suggests that the norepinephrine transporter also transports some dopamine as well, since dopamine is inactivated by norepinephrine reuptake in the prefrontal cortex

Prefrontal cortex

The prefrontal cortex is the anterior part of the frontal lobes of the brain, lying in front of the motor and premotor areas.This brain region has been implicated in planning complex cognitive behaviors, personality expression, decision making and moderating correct social behavior...

, which largely lacks dopamine transporters, therefore SNRIs can increase dopamine neurotransmission in this part of the brain.

Most SNRIs including venlafaxine, desvenlafaxine, and duloxetine, are several fold more selective for serotonin over norepinephrine, while milnacipran is three times more selective for norepinephrine than serotonin.
Elevation of norepinephrine levels is thought to be necessary for an antidepressant to be effective against neuropathic pain, a property shared with the older tricyclic antidepressants (TCAs), but not with the SSRIs.

Comparison to SSRIs

The SNRIs were developed more recently than the SSRIs and as a result there are relatively few of them. However, the SNRIs are among the most widely used antidepressants today. In 2009 Cymbalta and Effexor were the 11th and 12th most prescribed branded drugs in the United States. This translates to the 2nd and 3rd most common antidepressants, behind Lexapro (#5). In some studies, SNRI's demonstrated slightly higher antidepressant efficacy than the SSRIs (response rates 63.6% versus 59.3%). However, in one study escitalopram had a superior efficacy profile to venlafaxine. It is not clear what the reasons were for this unexpected anomaly. The side effects of SNRIs are reported to be slightly less severe in comparison to the SSRIs as well.
One of the major complaints that many users of SSRIs have is the negative sexual side effects that can be very difficult to treat.http://www.modernpsychiatry.org/sexual_sideeffects_of_ssris.htm Although SNRIs can have similar side effects, many of them can have the opposite effect of increased libido. Wellbutrin

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...

has had official studies done,http://www.mcmanweb.com/you_antidepressant.html and Strattera and Savella have commonly been reported as increasing libido in both men and women, even though studies have contradicted these reports.http://www.webmd.com However, the individuals who reported increased sexual functioning also tended to report increased anxiety, heart rate, blood pressure, and other negative effects associated with adrenaline increase.

Side effects

Because the SNRIs and SSRIs both act similarly to elevate serotonin levels, they subsequently share many of the same side effects, though to varying degrees. The most common include loss of appetite, weight, and sleep. There may also be drowsiness, dizziness, fatigue, headache, mydriasis

Mydriasis

Mydriasis 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...

, nausea/vomiting, sexual dysfunction, and urinary retention. There are two common sexual side effects: diminished interest in sex (libido) and difficulty reaching climax (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...

), which are usually somewhat milder with the SNRIs in comparison to the SSRIs. Nonetheless, sexual side effects account for lack of compliance with both SSRIs and SNRIs.

While tricyclic antidepressants also produce similar sexual side effects as SNRIs, discontinuation of TCAs is more often due to the other side effects (like cardiovascular effects). Also Amitriptyline

Amitriptyline

Amitriptyline 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...

(a TCAs) is more commonly associated with orthostatic hypotension

Orthostatic hypotension

Orthostatic 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...

.

Elevation of norepinephrine levels can sometimes cause anxiety, mildly elevated pulse, and elevated blood pressure. People at risk for hypertension and heart disease should have their blood pressure monitored.

Discontinuation syndrome

As with SSRIs, the abrupt discontinuation of an SNRI usually leads to withdrawal

Withdrawal

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...

, or "discontinuation 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...

", which could include states of anxiety

Anxiety

Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...

and other symptoms. It is therefore recommended that users seeking to discontinue an SNRI slowly taper the dose under the supervision of a professional. Discontinuation syndrome has been reported to be markedly worse for 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...

when compared to other SNRIs. Accordingly, as 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...

is related to venlafaxine, the same conditions apply. This is likely due to venlafaxine's relatively short half-life

Half-life

Half-life, abbreviated t½, is the period of time it takes for the amount of a substance undergoing decay to decrease by half. The name was originally used to describe a characteristic of unstable atoms , but it may apply to any quantity which follows a set-rate decay.The original term, dating to...

and therefore rapid clearance upon discontinuation.

Contraindications

Due to the effects of increased norepinephrine levels and therefore higher adrenergic

Adrenergic

An adrenergic agent is a drug, or other substance, which has effects similar to, or the same as, epinephrine . Thus, it is a kind of sympathomimetic agent...

activity, pre-existing hypertension should be controlled before treatment with SNRIs and blood pressure periodically monitored throughout treatment. Duloxetine has also been associated with cases of hepatic failure and should not be prescribed to patients with chronic alcohol use or liver disease.

SNRIs should be taken with caution when using St John's wort

St John's wort

St John's wort is the plant species Hypericum perforatum, and is also known as Tipton's Weed, Chase-devil, or Klamath weed....

as the combination can lead to the potentially fatal 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...

. They are contraindicated with dextromethorphan

Dextromethorphan

Dextromethorphan 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...

, tramadol

Tramadol

, cyclobenzaprine

Cyclobenzaprine

Cyclobenzaprine is a muscle relaxant medication used to relieve skeletal muscle spasms and associated pain in acute musculoskeletal conditions. It is the most well-studied drug for this application, and it also has been used off-label for fibromyalgia treatment.- Mechanism of action :The mechanism...

, meperidine/pethidine, and propoxyphene as well. They should also never be taken within 14 days of any other antidepressant, especially the monoamine oxidase inhibitor

Monoamine 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....