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Amitriptyline Review Article

 

Around the world, about 10% of people have or will suffer from depression at some point in their lifetimeAmitriptyline is an antidepressant that belongs to the tricylic antidepressant class of drugs. It affects chemical in the brain that may eventually become unbalanced and lead to depression. It is used to alleviate the symptoms of depression which include feelings of worthlessness, sadness, or guilt; tiredness; changes in appetite; loss of interest in daily activities; insomnia; sleeping too much; and though of suicide or death. Amitriptyline is one of the most clinically valuable antidepressant drugs.This drug is also used occasionally to ease certain types of pain. Amitriptyline is the most commonly used tricyclic antidepressant. Aside from decreasing depressive symptoms, it also gives relief to tension headaches, migraines, schizophrenic symptoms, and anxiety attacks. The main side effects of the drug are dry mouth and drowsiness. Other common side effects include changes in appetite, weight gain, muscle stiffness, constipation, nausea, nervousness, blurred vision, dizziness, urinary retention, changes in sexual function, and insomnia.

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DEPRESSION AND ITS MOLECULAR BASIS

Depression is a psychiatric condition affecting a very large part of the population around the world. Diagnostic symptoms of depression include dysphoria, anguish, anhedonia, and at least three of the following symptoms: disturbed sleep, loss of appetite and weight, loss of energy, decreased libido, psychomotor agitation (restlessness), psychomotor retardation (slowing down of thoughts and actions), difficulty in concentrating, indecisiveness, low self-esteem, pessimism, guilt, and thoughts about dying and suicide (Kandel et al., 2000). Continue reading...


Depression is classified in two types: unipolar, where the patient is always depressed, and bipolar, where the patient fluctuates between two opposing states: mania (excessive euphoria and enthusiasm) and depression.

Depression is one of the conditions for which the underlying causes are not very clear. The most accepted theory of depression is the “Monoamine Theory” also referred to by the name of “Biogenic Amine Theory”. Amines are organic compounds that contain nitrogen while biogenic amines are amines produced by plants or animals. Monoamines are amines that contain one amino group in their molecular structure. Monoamine and biogenic amines in this context refer to neurotransmitters and include dopamine, adrenaline, noradrenaline, serotonin, and histamine.

Neurons (cells that about half of the human brain consists of and are responsible for the transmission of information) communicate with each other by the transmission of molecules called neurotransmitters. There are several types of neurotransmitters. The Monoamine Theory of depression holds that depression is represented by a decreased availability of either or both of two monoamines: serotonin (also called 5-hydroxytryptamine, abbreviated 5-HT) and noradrenaline (abbreviated NA, also called norepinephrine). Obviously a decrease in the availability of any neurotransmitter would cause an inefficient communication between neurons. The neurons that use the above mentioned neurotransmitters are the serotonergic (in the case of 5-HT) and the noradrenergic (in the case of NA) neurons. But these neurons are in turn parts of greater structures of the brain: the serotonergic pathways (in the case of serotonergic neurons) and the noradrenergic pathways (in the case of noradrenergic neurons). These “pathways” are in fact collective connections of neurons which give the opportunity to neurons to function cooperatively in order for certain physiological, motor, cognitive, or emotional processes to take place. But this is the point where the situation gets even more complicated. These pathways, as well as other pathways of the brain, do not function independently of each other but they are interconnected and function co-dependently. Put together, these facts mean that a deficiency in a neurotransmitter could result not only in the dysfunction of their respective neuronal pathways but also in the dysfunction of other pathways in the brain.

What current psychopharmacological approaches to depression are based on, is that the administration of certain drugs that increase the availability of the amines 5-HT and/or NA in the synaptic clefts (i.e. the regions between connected neurons and where neurotransmitters are released from one neuron and picked up by others) alleviates the symptoms of depression. Of the drugs that increase the levels of both 5-HT and NA in the synaptic cleft the most widely used is amitriptyline, which is generally accepted to be one of science’s most valuable therapeutic tools against depression.

AMITRIPTYLINE AND ITS MECHANISMS OF ACTION

Amitriptyline is a tricyclic antidepressant. TCA is a type of antidepressants called so because of the three rings of atoms they harbour in their molecular structure- see figure 1.

Amitriptyline's chemical structure

Figure 1: The molecular structure of amitriptyline. The three rings of atoms in its structure are what classify it as a tricyclic antidepressant.

Before discussing amitriptyline’s mechanisms of action, the molecular mechanisms of neurotransmission need to be understood.

Neurotransmitters (abbreviated NTs) are synthesised in neuronal cells. Once synthesised, they are transported by synaptic vesicles to the synaptic terminal; this is the region in the neuron that is close to the synaptic cleft. Once an action potential arrives at the neuron and reaches the synaptic terminal, vesicles release their contents in the synaptic cleft. Because the neuron that transmits the NTs comes “before” the synapse in the path of the NTs, it is called a “presynaptic neuron”. The released NTs can then go and bind to special receptors on adjacent neurons; an event that triggers signalling mechanisms that can bring about various effects. The neurons that receive the NTs come “after” the synapse in the path of the NTs, so they are called “postsynaptic neurons”. The stimulation of the receptors ends when the presynaptic neuron reuptakes the NTs via special proteins called transporters. Once reuptaken, NTs can be utilised again for the same cycle of events.

Amitriptyline’s structure is such that it can bind to the binding sites of both 5-HT and NA transporters. But the binding of amitriptyline to the transporters can “saturate” the transporters, making them unavailable to 5-HT and NA (so, in pharmacological terms, amitriptyline is said to “compete” these neurotransmitters for their transporters’ binding sites). 5-HT and NA that “loose their ride” and don’t manage to get reuptaken by the transporters are consequently left for longer periods to be freely suspended in the synaptic cleft. This means that they are exposed for longer periods to the receptors of postsynaptic neurons. The receptors are thus left stimulated for longer, and this way they can also induce their molecular signalling mechanisms for longer. This leads to the therapeutic effects of amitriptyline. Figure 2 summarizes these events.

Neurotransmission and amitriptyline's mechanism of action

Figure 2: Amitriptyline, symbolised here by “X”, blocks the reuptake of 5-HT and NA and so prolongs their exposure to the receptors and the signalling mechanisms that they stimulate.

CLINICAL TRIALS
There have been hundreds of clinical trials for amitriptyline with positive results. In fact amitriptyline is widely being prescribed today for the treatment of depression. The only other type of antidepressants that “competes” with amitriptyline in popularity of clinical use are the selective serotonin reuptake inhibitors (SSRIs). As their name suggests, SSRIs inhibit the reuptake of 5-HT. This is also done by amitriptyline; though, unlike amitriptyline, SSRIs do not significantly affect the functioning of other NTs, including NA (hence the “selective” in their name).

A series of comprehensive systematic reviews of randomised clinical trials comparing the effects of amitriptyline against placebo and other types of antidepressants all point out to the same conclusion: that amitriptyline has slightly more potent antidepressant effects than other TCAs and other antidepressants such as SSRIs (Barbui and Hotopf, 2001, Barbui et al., 2004, Guaiana et al., 2007). On the other hand, however, it also has slightly more apparent side effects than the SSRIs. One of the most serious problems associated with amitriptyline is that a dose only slightly higher than the therapeutic one can be dangerous. These findings suggest that amitriptyline is a more potent drug, and that it should be considered the most appropriate in cases where patients suffer severe depression and do not pose a high risk of self-harm.

SIDE EFFECTS
Side effects of amitriptyline are common but mild. They include dry mouth, blurred vision, constipation, urinary retention, palpitations, and, sometimes, sedation.

PRECAUTIONS AND SAFETY
Because amitriptyline sometimes causes sedation, users of amitriptyline should be careful if they need to drive, operate heavy machinery, or perform any other task that could put them and others at any risk of injury. Co-administration with alcohol, anaesthetic agents, or antipsychotic drugs is contraindicated (Rang et al., 2007). The potential overdose of this drug is represented by only a 5 times higher dosage than the therapeutically effective dose (Feldman et al., 1997) - so care should be taken to avoid accidental overdose.

References
Barbui C., Guaiana G., Hotopf M., 2004, Amitriptyline for inpatients and SSRIs for outpatients with depression? Systematic review and meta-regression analysis, Pharmacopsychiatry; 37(3):93-7.

Barbui C., Hotopf M., 2001, Amitriptyline v. the rest: still the leading antidepressant after 40 years of randomised controlled trials, Br J Psychiatry.; 178:129-44.

Feldman R. S., Meyer J. S., Quenzer L. F., 1997, Principles of Neuropsychopharmacology, Sinauer Associates Inc.

Guaiana G., Barbui C., Hotopf M., 2007, Amitriptyline for depression, Cochrane Database Syst Rev.; (3):CD004186.

Kandel E., Schwartz J., Jessell T., 2000, Principles of Neural Science (Fourth Edition), McGraw-Hill Medical.

Rang H. P., Dale M. M., Ritter J. M., Flower R. J., 2007, Rang & Dale's Pharmacology (Sixth Edition), Churchill Livingstone.


 

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