Serotonin and norepinephrine reuptake inhibitors

Serotonin norepinephrine reuptake inhibitors, or SNRIs, are mainly used to treat major depressive disorder. This disorder causes a persistent feeling of sadness and loss of interest in everyday activities. Even though the exact cause of depression is still unknown, there's some evidence that suggests it’s related to low levels of neurotransmitters like serotonin, norepinephrine, and dopamine. Serotonin norepinephrine reuptake inhibitors work by increasing the levels of serotonin and norepinephrine to alleviate the symptoms of depression.

Alright, now within the brain, there are many different types of neurons, but we’re going to focus only on two: serotonergic neurons which produce serotonin, and noradrenergic neurons which produces norepinephrine. Each of these neurons synthesizes and stores their neurotransmitters in small vesicles. So, when an action potential reaches the presynaptic membrane, these vesicles fuse with the membrane, releasing neurotransmitters in the synaptic cleft. Once released, serotonin or 5-HT binds to 5-HT2 receptors on the postsynaptic membrane, thereby increasing neural stimulation and regulating mood, feeding, and reproductive behavior. On the other hand, norepinephrine binds to norepinephrine receptors on the postsynaptic membrane, boosting alertness. As long as there’s a high enough concentration of neurotransmitters in the synaptic cleft, the postsynaptic neurons will continue to fire. Now, serotonergic neurons on their presynaptic membrane have serotonin transporters or SERT, while noradrenergic neurons have norepinephrine transporters or NET. These membrane proteins transport the serotonin and norepinephrine in the synaptic cleft back into presynaptic neurons. This leads to decreased neurotransmitter concentration within the synaptic cleft, causing the postsynaptic neurons to stop firing.

So, in conditions such as major depressive disorder, where there are low levels of serotonin and norepinephrine, SNRIs can be used. Common medications in this class include duloxetine, venlafaxine, and desvenlafaxine, which is actually an active metabolite of venlafaxine, milnacipran, and levomilnacipran. SNRIs bind to serotonin and norepinephrine transporters and inhibit them, leading to increased levels of these neurotransmitters within their synaptic clefts. Other conditions that can be treated with SNRIs include anxiety and neuropathic pain like peripheral neuropathy. For medication specific indications, duloxetine can be used to treat urinary incontinence, which is an uncontrollable leakage of urine; and fibromyalgia, which is a condition characterized by chronic muscle pain, fatigue, and sleep problems. On the other hand, venlafaxine is indicated in social anxiety, panic disorders, post-traumatic stress disorder or PTSD and obsessive-compulsive disorder or OCD. Lastly, venlafaxine can treat postmenopausal hot flashes, which are sudden feelings of heat, usually most intense over the face, neck, and chest.

Side effects of SNRIs include insomnia, nausea and sexual dysfunctions. Also, due to increased levels of norepinephrine, SNRIs can cause high blood pressure, sweating, and headaches. The most dangerous, however, are suicidal ideations, especially in individuals under 25, and serotonin syndrome, which is a life-threatening condition caused by serotonin accumulation and over stimulation of the nervous system. This syndrome is characterized by skin flushing, hyperthermia, agitation, muscle rigidity, seizure, and coma. It usually occurs in individuals treated with a combination of SNRIs and other antidepressants that increase serotonin level, such as monoamine oxidase inhibitors. Treatment of serotonin syndrome consists of administration of benzodiazepines and supportive care, and in severe cases administration of cyproheptadine, which is an antihistamine that can also block 5HT2 receptors. If SNRIs are discontinued abruptly, some people can experience withdrawal syndromes like irritability, headaches, and insomnia. For medicine specific side effects, venlafaxine is an inhibitor of cytochrome P450 enzymes. These liver enzymes are responsible for the metabolism of a variety of drugs and toxins in our body. So, when combined with other drugs that are metabolized by cytochrome P450 enzymes, such as benzodiazepines, SSRIs will reduce their rate of elimination and cause them to build up in the body. Lastly, duloxetine can potentially cause liver damage, so it’s hepatotoxic.