Classes of Antidepressants Drugs

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Depression is a disorder where the patient is unable to function normally.  The patient may lack the ability to enjoy activities that are “fun” or pleasurable.  In addition, they may be unable to eat, work, or sleep.  Depressed individuals usually appear thin and are emotionless for quite some time (5 weeks at least).  Treatment can come in the form of psychological interventions and antidepressants.  The basis for treating depression revolves around the amine hypothesis.  Though there are other theories, pharmaceutical companies have developed antidepressants along the lines of this theory which states that depression is the result of the lack of amine neurotransmitters (e.g. norepinephrine, serotonin) within neurons of the brain.  This was discovered in the early 1950’s when the drug reserpine was found to induce symptoms of depression by depleting internal stores of amine transmitters in neurons.  As a result, less are available to be released into the synapse (area between neurons) for neurotransmission, leading to a loss of pleasure and consequently depression.

 

Currently, there are several of classes of antidepressants.  All generally work on the same principle of potentiating serotonin and/or norepinephrine in the synapse between neurons thereby enhancing neurotransmission.  These drugs are tricyclics, heterocyclics, selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), and atypical antidepressants.  Discussion of their mechanism of action and side effects are shown below.

 

The Tricyclic Class

The tricyclic class of antidepressants is the oldest class used to treat depression (i.e. first generation).  They are called as such due to their chemical structure.  The prototypical drugs of this class are imipramine (Tofranil) and amitriptyline (Elavil).  The purported mechanism of action is to inhibit reuptake of serotonin and norepinephrine back into the neuron. This produces increases in the levels of these neurotransmitters in the synapse, eventually leading to prolonged neuroactivation.  Though these drugs can be effective, their side effect profile has led to development of newer, safer drugs.  These side effects include sedation, tremors, insomnia, blurred vision, constipation, hypotension (low blood pressure), arrhythmias (irregular heart beat), seizures and weight gain.  Suicide is also a major concern as are withdrawal symptoms.  Despite these effects, some are still in use today because of their efficacy.

 

Heterocyclics or tetracyclics are newer drugs that are similar to tricyclic antidepressants.  These contain fewer side effects.   Some FDA approved drugs include amoxapine (Asendin), maprotiline (Ludiomil), trazodome (Desyrel) and bupropion (Wellbutrin).  Unlike the first generation, the mechanism of action varies from drug to drug, but they generally block reuptake of the neurotransmitters norepinephrine, epinephrine and/or dopamine.  Though they contain fewer side effects, the effects can still be dangerous such as sedation, drowsiness, seizures, dizziness, dry mouth, cardiotoxicity and tremors.  Seizures are a major concern when these drugs are used in high concentrations or in the event of overdose.

 

SSRIs and SNRIs are newer antidepressants that have minimal toxicity with respect to the autonomic nervous system which controls heart rate, digestion and sleep in addition to other unconscious behaviors.  Their structures are different from tricyclic antidepressants as well as each other.  As their names state, they are selective for either serotonin reuptake, or serotonin and norepinephrine reuptake.  Like tricyclics, their main action is to block reuptake to increase neurotransmitter levels in the synapse.  Fluoxetine (Prozac) has been the most successful antidepressant in terms of sales and is the prototypical SSRI.  Duloxetine (Cymbalta) similarly is the nominal SNRI.  As stated earlier, these antidepressants have less autonomic side effect, but do present a distinct set of side effects, which include insomnia, gastrointestinal discomfort, rash, acute anxiety, weight gain, and decreased sexual function and libido.  Withdrawal symptoms may be present with SNRIs, which necessitates the weaning of drug when depression is finally treated.  Overdose rarely results in major problems in adults, but they do seriously increase suicidal thoughts in children when used.  As such, monitoring drug use in children drugs is crucial.   Aside from discussed concerns, these drugs continue to be the most utilized and prescribed.

 

MAOIs are different from the other antidepressants in terms of their mechanism of action, and they are generally used when other types of antidepressants fail to alleviate symptoms of depression. They do not block reuptake, but rather block an enzyme that is found in the synapse, monoamine oxidase, that metabolizes or breaks down serotonin, norepinephrine and dopamine (MAO-A subtype).  There are two types of the enzyme, MAO-A and MAO-B.  By inhibiting breakdown, they increase levels of these transmitters in the synapse for neurotransmission.  Older MAOIs have been found to be dangerous because they inhibit the MAO-B subtype (as well as the MAO-A subtype), which may lead to hypertension, tremors, hyperthermia and shock.  This is usually caused by the buildup of tyramine, a molecule found in variety of founds such as cheese and wine which is usually broken down by MAO-B.  Therefore dietary monitoring is needed with older MAOIs. Some commonly used MAOIs include phenelzine (Nardil) and tranylcypromine (Parnate).

 

Atypical Antidepressants

Atypical antidepressants are the newest type of drugs developed to treat depression and they have various modes of action.  They include a serotonin reuptake enhancer, selective norepinephrine inhibitor and a melatonin receptor agonist.  They have great potential and may become the treatments of the future.

 

Tianeptine (Stablon) is a selective serotonin reuptake enhancer.  As its name states, it increases reuptake rather than inhibits it.  This may seem odd, but research has shown that it does provide relief to some depressed patients.   It has also been shown to increase dopamine levels in the nucleus accumbens by an unknown mechanism.  This area of the brain is known for pleasure and therefore, increases in dopamine concentration are thought to enhance mood.  Since it is similar to stimulants however, there is potential for this drug to be abused and overused.  Patient monitoring is needed to allay these concerns.

 

Norepinephrine reuptake inhibitors (NRIs) are like SSRIs, except they are selective for reuptake inhibition of norepinephrine rather than serotonin.  They are more regularly prescribed for ADHD, but have been found to provide relief in depression.  Some typical NRIs include atomoxetine (Strattera) and Mazindol (Mazanor).  By selectively inhibiting norepinephrine reuptake, research has found that they can improve focus and concentration, areas where depressed patients have deficits.  NRIs have side effects that resemble stimulants such as hypertension, hyperthermia (high body temperature), insomnia and agitation, however they have not been found to be addictive.  Overdose can lead to hypertensive crisis such as irregular heartbeat, muscle twitching, twitch, fainting and shock.

 

Agolamelatine (Valdoxin) is an agonist at melatonin receptors and an antagonist at serotonin receptors (5-HT2C subtype).  This mixed action is proposed to increase neurotransmission in the frontal cortex where some dopamine and norepinephrine neurons reside.  Melatonin receptors are important in sleep and studies have shown enhanced sleep quality with agolametine.  By blocking the 5-HT2C receptor subtype, the inhibition allows more serotonin to be released from neurons. Increased release of serotonin into the synapse enhances neurotransmission.   Agolametaine is particularly interesting because it lacks the side effects of other antidepressants including SSRIs, and may be the best antidepressant available, but like any new product, “a wait-and-see” approach is needed as more data accumulates.

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