| Serotonin–norepinephrine reuptake inhibitor | |
|---|---|
| Drug class | |
Duloxetine, an example of an SNRI.
| |
| Class identifiers | |
| Synonyms | Selective Serotonin–noradrenaline reuptake inhibitor; SNaRI |
| Use | Depression; Anxiety; Pain; Obesity; Menopausal symptoms |
| Biological target | Serotonin transporter; Norepinephrine transporter |
Serotonin–norepinephrine reuptake inhibitors (SNRIs) are a class of antidepressant drugs that treat major depressive disorder (MDD) and can also treat anxiety disorders, obsessive–compulsive disorder (OCD), attention-deficit hyperactivity disorder (ADHD), chronic neuropathic pain, fibromyalgia syndrome (FMS), and menopausal symptoms.
SNRIs are monoamine reuptake inhibitors; specifically, they inhibit the reuptake of serotonin and norepinephrine. These neurotransmitters play an important role in mood. SNRIs can be contrasted with the more widely used selective serotonin reuptake inhibitors (SSRIs), which act upon serotonin only.
The human serotonin transporter (SERT) and norepinephrine transporter (NET) are membrane transport proteins that are responsible for the reuptake of serotonin and norepinephrine. Dual inhibition of serotonin and norepinephrine reuptake can offer advantages over other antidepressant drugs by treating a wider range of symptoms.
SNRIs, along with SSRIs and norepinephrine reuptake inhibitors (NRIs), are second-generation antidepressants. Over the past two decades, second-generation antidepressants have gradually replaced first-generation antidepressants, such as tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs), as the drugs of choice for the treatment of MDD due to their improved tolerability and safety profile.
A closely related type of drug is a serotonin–norepinephrine releasing agent (SNRA), for instance the withdrawn appetite suppressant fenfluramine/phentermine (Fen-Phen). SNRAs primarily induce the release rather than inhibit the reuptake of serotonin and norepinephrine.
Types
Timeline of approved SNRIs.
- Atomoxetine—a norepinephrine-predominant SNRI used in the treatment of ADHD and, off-label, major depression. Was approved by FDA in 2002. Originally considered to be a selective norepinephrine reuptake inhibitor, but research subsequently revealed that it significantly inhibits the reuptake of serotonin at clinical dosages as well.
- Desvenlafaxine—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 and was then the third approved SNRI.
- Duloxetine has been approved for the treatment of depression and neuropathic pain 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 that can lead to acute hepatitis or other diseases in certain at risk patients. Currently, the risk of liver damage appears to be only for patients already at risk, unlike the antidepressant nefazodone, which, though rare, can spontaneously cause liver failure in healthy patients. Duloxetine is also approved for major depressive disorder (MDD), generalized anxiety disorder (GAD), diabetic neuropathy, chronic musculoskeletal pain, including chronic osteoarthritis pain and chronic low back pain.
- Levomilnacipran—the levorotating isomer of milnacipran. Under development for the treatment of depression in the United States and Canada, it was approved by the FDA for treatment of MDD in July 2013.
- Milnacipran—shown to be significantly effective in the treatment of depression and fibromyalgia. The Food and Drug Administration (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. It was first introduced in France in 1996.
- Sibutramine—an SNRI, which, instead of being developed for the treatment of depression, was widely marketed as an appetite suppressant for weight loss purposes. Sibutramine was the first drug for the treatment of obesity to be approved in 30 years. It has been associated with increased cardiovascular events and strokes and has been withdrawn from the market in several countries and regions including the United States in 2010.
- Tramadol—a dual weak opioid and SNRI. It was approved by the FDA in 1995, though it has been marketed in Germany since 1977. The drug is used to treat acute and chronic pain. It has shown effectiveness in the treatment of fibromyalgia, though it is not specifically approved for this purpose. The drug is also under investigation as an antidepressant and for the treatment of neuropathic pain. It is related in chemical structure to venlafaxine.
- Venlafaxine—the first and most commonly used SNRI. It was introduced by Wyeth in 1994. The reuptake effects of venlafaxine are dose-dependent. At low doses (<150 acts="" at="" day="" doses="" it="" mg="" moderate="" nbsp="" on="" only="" serotonergic="" transmission.="">150 mg/day), it acts on serotonergic and noradrenergic systems, whereas at high doses (>300 mg/day), it also affects dopaminergic neurotransmission.
History
In 1952, iproniazid, an antimycobacterial agent, was discovered to have psychoactive properties while researched as a possible treatment for tuberculosis.
Researchers noted that patients given iproniazid became cheerful, more
optimistic, and more physically active. Soon after its development,
iproniazid and related substances were shown to slow enzymatic breakdown
of serotonin, dopamine, and norepinephrine via inhibition of the enzyme monoamine oxidase. For this reason, this class of drugs became known as monoamine oxidase inhibitors, or MAOIs. During this time development of distinctively different antidepressant agents was also researched. Imipramine became the first clinically useful tricyclic antidepressant
(TCA). Imipramine was found to affect numerous neurotransmitter systems
and to block reuptake of norepinephrine and serotonin from the synapse, therefore increasing the levels of these neurotransmitters. Use of MAOIs and TCAs gave major advances in treatment of depression but their use was limited by unpleasant side effects and significant safety and toxicity issues.
Throughout the 1960s and 1970s, the catecholamine
hypothesis of emotion and its relation to depression was of wide
interest and that the decreased levels of certain neurotransmitters,
such as norepinephrine, serotonin, and dopamine might play a role in the
pathogenesis of depression. This led to the development of fluoxetine,
the first SSRI. The improved safety and tolerability profile of the
SSRIs in patients with MDD, compared with TCAs and MAOIs, represented
yet another important advance in the treatment of depression.
Since the late 1980s, SSRIs have dominated the antidepressant
drug market. Today, there is increased interest in antidepressant drugs
with broader mechanisms of action that may offer improvements in efficacy and fewer adverse effects. In 1993, a new drug was introduced to the US market called venlafaxine, a serotonin-norepinephrine reuptake inhibitor. Venlafaxine was the first compound described in a new class of antidepressive substances called phenylethylamines.
These substances are unrelated to TCA and other SSRIs. Venlafaxine
blocks the neuronal reuptake of serotonin, noradrenaline, and, to a
lesser extent, dopamine in the central nervous system.
In contrast with several other antidepressant drugs, venlafaxine can
induce a rapid onset of action mainly due to a subsequent norepinephrine
reuptake inhibition.
Timeline of development of antidepressant agents.
Mechanism of action
Monoamines are connected to the pathophysiology
of depression. Symptoms may occur because concentrations of
neurotransmitters, such as norepinephrine and serotonin, are
insufficient, leading to downstream changes. Medications for depression affect the transmission of serotonin, norepinephrine, and dopamine. Older and more unselective antidepressants like TCAs and MAOIs inhibit the reuptake or metabolism of norepinephrine and serotonin in the brain, which results in higher concentrations of neurotransmitters.
Antidepressants that have dual mechanisms of action inhibit the
reuptake of both serotonin and norepinephrine and, in some cases,
inhibit with weak effect the reuptake of dopamine.
Antidepressants affect variable neuronal receptors like muscarinic-cholinergic, α1- and α2-adrenergic, and H1-histaminergic receptors, and sodium channels in the cardiac muscle, leading to decreased cardiac conduction and cardiotoxicity. Selectivity of antidepressant agents are based on the neurotransmitters that are thought to influence symptoms of depression.
Drugs that selectively block the reuptake of serotonin and
norepinephrine effectively treat depression and are better tolerated
than TCAs. TCAs have comprehensive effects on various neurotransmitters
receptors, which leads to lack of tolerability and increased risk of
toxicity.
Tricyclic antidepressants
Inhibiting
the reuptake transport protein results in increased concentrations of
serotonin and norepinephrine in the synaptic clefts, leading to
improvement of depression symptoms.
TCAs were the first medications that had dual mechanism of action.
The mechanism of action of tricyclic secondary amine antidepressants is
only partly understood. TCAs have dual inhibition effects on
norepinephrine reuptake transporters and serotonin reuptake
transporters.
Increased norepinephrine and serotonin concentrations are obtained by
inhibiting both of these transporter proteins. TCAs have substantially
more affinity for norepinephrine reuptake proteins than the SSRIs. This
is because of a formation of secondary amine TCA metabolites.
In addition, the TCAs interact with adrenergic receptors.
This interaction seems to be critical for increased availability of
norepinephrine in or near the synaptic clefts. Actions of
imipramine-like tricyclic antidepressants have complex, secondary
adaptions to their initial and sustained actions as inhibitors of
norepinephrine transport and variable blockade of serotonin transport.
Norepinephrine interacts with postsynaptic α and β adrenergic receptor
subtypes and presynaptic α2 autoreceptors. The α2 receptors include presynaptic autoreceptors which limit the neurophysiological activity of noradrenergic neurons in the central nervous system. Formation of norepinephrine is reduced by autoreceptors through the rate-limiting enzyme tyrosine hydroxylase, an effect mediated by decreased cyclic AMP-mediated phosphorylation-activation of the enzyme. α2 receptors also cause decreased intracellular cyclic AMP expression which results in smooth muscle relaxation or decreased secretion. TCAs activate a negative feedback
mechanism through their effects on presynaptic receptors. One probable
explanation for the effects on decreased neurotransmitter release is
that, as the receptors activate, inhibition of neurotransmitter release
occurs (including suppression of voltage-gated Ca2+ currents and activation of G protein-coupled receptor-operated K+
currents). Repeated exposure of agents with this type of mechanism
leads to inhibition of neurotransmitter release, but repeated
administration of TCAs finally leads to decreased responses by α2 receptors.
The desensitization
of these responses may be due to increased exposure to endogenous
norepinephrine or from the prolonged occupation of the norepinephrine
transport mechanisms (via an allosteric effect). The adaptation allows
the presynaptic synthesis and secretion of norepinephrine to return to,
or even exceed, normal levels of norepinephrine in the synaptic clefts.
Overall, inhibition of norepinephrine reuptake induced by TCAs, leads to
decreased rates of neuron firing (mediated through α2 autoreceptors), metabolic activity, and release of neurotransmitters.
TCAs do not block dopamine transport directly, but might
facilitate dopaminergic effects indirectly by inhibiting dopamine
transport into noradrenergic terminals of the cerebral cortex.
Because they affect so many different receptors, TCAs have adverse
effects, poor tolerability, and an increased risk of toxicity.
Selective serotonin reuptake inhibitors
Selective
serotonin reuptake inhibitors (SSRIs) selectively inhibit the reuptake
of serotonin and are a widely used group of antidepressants. With increased receptors selectivity compared to TCAs, undesired effects like poor tolerability are avoided. Serotonin is synthesized from an amino acid called L-tryptophan. Active transport system regulates the uptake of tryptophan across the blood–brain barrier.
Serotonergic pathways are classified into two main ways in the brain;
the ascending projections from the medial and dorsal raphe and the
descending projections from the caudal raphe into the spinal cord.
Selective norepinephrine reuptake inhibitors
Noradrenergic neurons are located in two major regions in the brain. These regions are locus coeruleus and lateral tegmental.
With administration of selective NRIs, neuronal activity in locus
coeruleus region is induced because of increased concentration of
norepinephrine in the synaptic cleft. This results in activation of α2 adrenergic receptors, as discussed previously.
Assays have shown that selective NRIs have insignificant penchant for mACh, α1 and α2 adrenergic, or H1 receptors.
Dual serotonin and norepinephrine reuptake inhibitors
Agents
with dual serotonin and norepinephrine reuptake inhibition (SNRIs) are
sometimes called non-tricyclic serotonin and norepinephrine reuptake
inhibitors. Clinical studies suggest that compounds that increase the
concentration in the synaptic cleft of both norepinephrine and serotonin
are more successful than single acting agents in the treatment of
depression.
Dual reuptake inhibitors have low affinity at neuronal receptors of the
other neurotransmitters, which have low adverse effects compared with
the TCAs. Nontricyclic antidepressants have improved potency and onset
action acceleration in antidepressant response than SSRIs alone, which
give the impression that synergism is an efficient property in mediating
antidepressant activity.
The non-tricyclic SNRIs have several important differences that
are based on pharmacokinetics, metabolism to active metabolites,
inhibition of CYP isoforms, effect of drug-drug interactions, and the half-life of the nontricyclic SNRIs.
Combination of mechanisms of action in a single active agent is an important development in psychopharmacology.
Structure activity relationship (SAR)
Aryloxypropanamine scaffold
Several
reuptake inhibitors contain an aryloxypropanamine scaffold. This
structural motif has potential for high affinity binding to biogenic
amine transports.
Drugs containing an aryloxypropanamine scaffold have selectivity
profile for norepinephrine and serotonin transporters that depends on
the substitution pattern of the aryloxy ring. Selective NRIs contain a
substituent in 2' position of the aryloxy ring but SSRIs contain a substituent
in 4' position of the aryloxy ring. Atomoxetine, nisoxetine and
reboxetine all have a substitution group in the 2' position and are
selective NRIs while compounds that have a substitution group in the 4'
position (like fluoxetine and paroxetine) are SSRIs. Duloxetine contains a phenyl group
fused at the 2' and 3' positions, therefore it has dual selective
norepinephrine and serotonin reuptake inhibitory effects and has similar
potencies for the both transporters. The nature of the aromatic
substituent also has a significant influence on the activity and
selectivity of the compounds as inhibitors of the serotonin or the
norepinephrine transporters.
Aryloxypropanamine scaffold and agents containing it.
Cycloalkanol ethylamine scaffold
Venlafaxine and desvenlafaxine contain a cycloalkanol ethylamine scaffold. Increasing the electron-withdrawing nature of the aromatic ring
provides more potent inhibitory effect of norepinephrine uptake and
improves the selectivity for norepinephrine over the serotonin
transporter.
Effects of chloro, methoxy and trifluoromethyl substituents in the
aromatic ring of cycloalkanol ethylamine scaffold were tested. The
results showed that the strongest electron-withdrawing m-trifluoromethyl
analogue exhibited the most potent inhibitory effect of norepinephrine
and the most selectivity over serotonin uptake. WY-46824, a piperazine-containing derivative, has shown norepinephrine and dopamine reuptake inhibition.
Further synthesis and testing identified WAY-256805, a potent
norepinephrine reuptake inhibitor that exhibited excellent selectivity
and was efficacious in animal models of depression, pain, and
thermoregulatory dysfunction.
Cycloalkanol ethylamine scaffold and agents containing it.
Milnacipran
Structure of milnacipran.
Milnacipran is structurally different from other SNRIs.
The SAR of milnacipran derivatives at transporter level is still
largely unclear and is based on in vivo efficacy that was reported in
1987. N-methylation of milnacipran in substituent group R4 and R5 reduces the norepinephrine and serotonin activity. Researches on different secondary amides in substitution groups R6 and R7
showed that π electrons play an important role in the interaction
between transporters and ligands. A phenyl group in substituent R6 showed effect on norepinephrine transporters. Substituent groups in R6 and R7 with allylic double bond showed significant improved effect on both norepinephrine and serotonin transporters. Studies show that introducing a 2-methyl group in substituent R3, the potency at norepinephrine and serotonin transporters are almost abolished. Methyl groups in substituent groups R1 and R2
also abolish the potency at norepinephrine and serotonin transporters.
Researchers found that replacing one of the ethyl groups of milnacipran
with an allyl moiety increases the norepinephrine potency. The pharmacophore of milnacipran derivatives is still largely unclear.
The conformation of milnacipran is an important part of its pharmacophore. Changing the SAR in milnacipran changes the stereochemistry of the compound and affects the norepinephrine and serotonin concentration. Milnacipran is marketed as a racemic mixture. Effects of milnacipran reside in the (1S,2R)-isomer and substitution of the phenyl group in the (1S,2R)-isomer has negative impact on norepinephrine concentration. Milnacipran has low molecular weight and low lipophilicity. Because of these properties, milnacipran exhibits almost ideal pharmacokinetics in humans such as high bioavailability, low inter-subject variability, limited liver enzyme
interaction, moderate tissue distribution and a reasonably long
elimination half-life. Milnacipran's lack of drug-drug interactions via cytochrome P450
enzymes is thought to be an attractive feature because many of the
central nervous system drugs are highly lipophilic and are mainly
eliminated by liver enzymes.
Future development of SAR
The application of an aryloxypropanamine scaffold has generated a number of potent MAOIs.
Before the development of duloxetine, the exploration of
aryloxypropanamine SAR resulted in the identification of fluoxetine and
atomoxetine. The same motif can be found in reboxetine where it is
constrained in a morpholine ring system. Some studies have been made where the oxygen in reboxetine is replaced by sulfur
to give arylthiomethyl morpholine. Some of the arylthiomethyl
morpholine derivatives maintain potent levels of serotonin and
norepinephrine reuptake inhibition. Dual serotonin and norepinephrine
reuptake inhibition resides in different enantiomers for arylthiomethyl
morpholine scaffold.
Possible drug candidates with dual serotonin and norepinephrine
reuptake inhibitory activity have also been derived from piperazine,
3-amino-pyrrolidine and benzylamine templates.
Clinical trials
Several
studies have shown that antidepressant drugs which have combined
serotonergic and noradrenergic activity are generally more effective
than SSRIs, which act upon serotonin reuptake by itself.
Serotonergic-noradrenergic antidepressant drugs may have a modest
efficacy advantage compared to SSRIs in treating major depressive
disorder (MDD), but are slightly less well tolerated.
Further research is needed to examine the possible differences of
efficacy in specific MDD sub-populations or for specific MDD symptoms,
between these classes of antidepressant drugs.
Data from clinical trials have indicated that SNRIs might have
pain relieving properties. Although the perception and transmission of
pain stimuli in the central nervous system have not been fully
elucidated, extensive data support a role for serotonin and
norepinephrine in the modulation of pain. Findings from clinical trials
in humans have shown these antidepressants can to reduce pain and
functional impairment in central and neuropathic pain conditions. This
property of SNRIs might be used to reduce doses of other pain relieving
medication and lower the frequency of safety, limited efficacy and
tolerability issues.
Clinical research data have shown in patients with GAD that the SNRI
duloxetine is significantly more effective than placebo in reducing
pain-related symptoms of GAD, after short-term and long-term treatment.
However, findings suggested that such symptoms of physical pain reoccur
in relapse situations, which indicates a need for ongoing treatment in
patients with GAD and concurrent painful physical symptoms.
Indications
SNRIs have been approved for treatment of the following conditions:
- Major depressive disorder (MDD)
- Posttraumatic stress disorder (PTSD)
- Generalized anxiety disorder (GAD)
- Social anxiety disorder (SAD)
- Panic disorder
- Neuropathic pain
- Fibromyalgia
- Chronic musculoskeletal pain
Pharmacology
Route of administration
SNRIs
are delivered orally, usually in the form of capsules. The drugs
themselves are usually a fine crystalline powder that diffuses into the
body during digestion.
Dosage
Dosages
fluctuate depending on the SNRI used due to varying potencies of the
drug in question as well as multiple strengths for each drug.
Mode of action
The
condition for which SNRIs are mostly indicated, major depressive
disorder, is thought to be mainly caused by decreased levels of
serotonin and norepinephrine in the synaptic cleft, causing erratic
signaling. Due to the monoamine hypothesis
of depression, which asserts that decreased concentrations of monoamine
neurotransmitters leads to depression symptoms, the following relations
were determined: "Norepinephrine may be related to alertness and energy
as well as anxiety, attention, and interest in life; [lack of]
serotonin to anxiety, obsessions, and compulsions; and dopamine to
attention, motivation, pleasure, and reward, as well as interest in
life." SNRIs work by inhibiting the reuptake of the neurotransmitters serotonin and norepinephrine. This results in an increase in the extracellular concentrations of serotonin and norepinephrine and, therefore, an increase in neurotransmission.
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.
Recent studies have shown that depression may be linked to increased inflammatory response,
thus attempts at finding an additional mechanism for SNRIs have been
made. Studies have shown that SNRIs as well as SSRIs have significant
anti-inflammatory action on microglia
in addition to their effect on serotonin and norepinephrine levels. As
such, it is possible that an additional mechanism of these drugs that
acts in combination with the previously understood mechanism exist. The
implication behind these findings suggests use of SNRIs as potential
anti-inflammatories following brain injury or any other disease where
swelling of the brain is an issue. However, regardless of the mechanism,
the efficacy of these drugs in treating the diseases for which they
have been indicated has been proven, both clinically and in practice.
Pharmacodynamics
Most SNRIs function alongside primary metabolites and secondary metabolites
in order to inhibit reuptake of serotonin, norepinepherine, and
marginal amounts of dopamine. For example, venlafaxine works alongside
its primary metabolite O-desmethylvenlafaxine to strongly inhibit
serotonin and norepinephrine reuptake in the brain. The evidence also
suggests that dopamine and norepinepherine behave in a
cotransportational manner, due to the inactivation of dopamine by
norepinephrine reuptake in the frontal cortex,
an area of the brain largely lacking in dopamine transporters. This
effect of SNRIs results in increased dopamine neurotransmission, in
addition to the increases in serotonin and norepinephrine activity.
Furthermore, because SNRIs are extremely selective, they have no
measurable effects on other, unintended receptors, in contrast to monoamine oxidase inhibition. Pharmaceutical tests have determined that use of both SNRIs or SSRIs can generate significant anti-inflammatory action on microglia, as well.
Activity profiles
| Compound | SERT | NET | ~Ratio (5-HT : NE) | ||
|---|---|---|---|---|---|
| Ki | IC50 | Ki | IC50 | ||
| Venlafaxine | 7.8 | 145 | 1,920 | 1420 | 1:30 |
| Des-venlafaxine | 40.2 | 47.3 | 558.4 | 531.3 | 1:14 |
| Duloxetine | 0.07 | 3.7 | 1.17 | 20 | 1:10 |
| Atomoxetine | 87[50] | 5.4 [50] | 1 : 0.06 (16 : 1) | ||
| Milnacipran | 8.44 | 151 | 22 | 68 | 1:1.6 |
| Levo-milnacipran | 11.2 | 19.0 | 92.2 | 10.5 | 1:2 |
| All of the Ki and IC50 values are nM. The 5-HT/NE ratio is based on IC50 values for the SERT and NET. | |||||
Pharmacokinetics
The half-life of venlafaxine
is about 5 hours, and with once-daily dosing, steady-state
concentration is achieved after about 3 days, though its active
metabolite desvenlafaxine lasts longer. The half-life of desvenlafaxine is about 11 hours, and steady-state concentrations are achieved after 4 to 5 days. The half-life of duloxetine is about 12 hours (range: 8-17 hours), and steady-state is achieved after about 3 days. Milnacipram has a half-life of about 6 to 8 hours, and steady-state levels are reached within 36 to 48 hours.
Contraindications
Due to the effects of increased norepinephrine levels and, therefore, higher noradrenergic
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. Patients suffering from coronary artery
disease should avoid the use of SNRIs. Furthermore, due to some SNRIs'
actions on obesity, patients with major eating disorders such as anorexia nervosa or bulimia should not be prescribed SNRIs.
Duloxetine and milnacipran are also contraindicated in patients with
uncontrolled narrow-angle glaucoma, as they have been shown to increase
incidence of mydriasis.
SNRIs should be taken with caution when using St John's wort, as the combination can lead to the potentially fatal serotonin syndrome. There is also a significant risk when combining SNRIs with dextromethorphan, tramadol, cyclobenzaprine, meperidine/pethidine, and propoxyphene. They should never be taken within 24-hours of any other antidepressant, especially with monoamine oxidase inhibitors
(MAOIs), as combinations of SNRIs with MAOIs can cause hyperthermia,
rigidity, myoclonus, autonomic instability with fluctuating vital signs,
and mental status changes that include extreme agitation progressing to
delirium and coma.
Side effects
Because
the SNRIs and SSRIs act in similar ways to elevate serotonin levels,
they share many side effects, though to varying degrees. The most common
side effects include loss of appetite, weight, and sleep, drowsiness,
dizziness, fatigue, headache, increase in suicidal thoughts,
nausea/vomiting, sexual dysfunction, and urinary retention. There are
two common sexual side effects: diminished interest in sex (libido) and
difficulty reaching climax (anorgasmia), which are usually somewhat milder with SNRIs compared to SSRIs.
Elevation of norepinephrine levels can sometimes cause anxiety, mildly
elevated pulse, and elevated blood pressure. However,
norepinephrine-selective antidepressants, such as reboxetine and
desipramine, have successfully treated anxiety disorders. People at risk for hypertension and heart disease should monitor their blood pressure.
Precautions
Starting an SNRI regimen
Due
to the extreme changes in noradrenergic activity produced from
norepinephrine and serotonin reuptake inhibition, patients that are just
starting an SNRI regimen are usually given lower doses than their
expected final dosing to allow the body to acclimate to the drug's
effects. As the patient continues along at low doses without any
side-effects, the dose is incrementally increased until the patient sees
improvement in symptoms without detrimental side-effects.
Discontinuation syndrome
As with SSRIs, the abrupt discontinuation of an SNRI usually leads to withdrawal, or "discontinuation syndrome", which could include states of anxiety
and other symptoms. Therefore, it is 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 when compared to other SNRIs. As such, as tramadol is related to venlafaxine, the same conditions apply. This is likely due to venlafaxine's relatively short half-life
and therefore rapid clearance upon discontinuation. In some cases,
switching from venlafaxine to fluoxetine, a long-acting SSRI, and then
tapering off fluoxetine, may be recommended to reduce discontinuation
symptoms.
Overdose
Causes
Overdosing
on SNRIs can be caused by either drug combinations or excessive amounts
of the drug itself. Venlafaxine is marginally more toxic in overdose
than duloxetine or the SSRIs.
Symptoms
Symptoms
of SNRI overdose, whether it be a mixed drug interaction or the drug
alone, vary in intensity and incidence based on the amount of medicine
taken and the individuals sensitivity to SNRI treatment. Possible
symptoms may include:
- Somnolence
- Coma
- Serotonin syndrome
- Seizures
- Syncope
- Tachycardia
- Hypotension
- Hypertension
- Hyperthermia
- Vomiting
Management
Overdose
is usually treated symptomatically, especially in the case of serotonin
syndrome, which requires treatment with cyproheptadine and temperature
control based on the progression of the serotonin toxicity. Patients are
often monitored for vitals and airways cleared to ensure that they are
receiving adequate levels of oxygen. Another option is to use activated
carbon in the GI tract in order to absorb excess neurotransmitter. It is important to consider drug interactions when dealing with overdose patients, as separate symptoms can arise.
Comparison to SSRIs
Because SNRIs were developed more recently than SSRIs,
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), the SSRI escitalopram. In some studies, SNRIs 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.
