Saturday, 27 August 2016

Depression and Anti-Depressant Medications: Assessing the Side-Effects of Standard Pharmacotherapy and the Efficacy of Natural Alternatives

The prevalence of depression has increased lately with more and more people being diagnosed with major depression. Most clinicians who have diagnosed people with depression usually prescribe antidepressants as a mode of treatment. Thus, most of the newly diagnosed patients do age while taking antidepressants, and this also implies that the cumulative side effects of the drugs do affect their wellbeing. The biological basis of depression is a sub-normal level of serotonin in the brain systems; and the drugs thus act to increase the serotonin levels back to normal levels or even to above-normal levels (Stahl & Schwartz, 2016). Nonetheless, the drugs have known side-effects which are discussed below, and shown to be unacceptable, especially in the long term. Moreover, there are other alternatives to antidepressants. Thus, antidepressant medications do have unacceptable side-effects which do harm the overall well-being of people suffering from depression hence necessitating the use of the other alternatives to antidepressants.
Common Anti-Depression Medications. Photo Credit: MedicalDaily.com
Depression
Depression is an affective disorder characterized by lethargy (loss of energy), anhedonia (loss of interest), feelings of inadequate self-worth, persistent pessimism, irritability, loss of appetite, suicidal thoughts, poor self-image, low self-esteem; and either insomnia or hypersomnia. Depending on the symptoms, and their severity, depression has been categorized into the following five main types; major depression, dysthymia, bipolar disorder, atypical depression, and seasonal depression. The diagnosis of depression is based on the criteria outlined by the DSM-V which qualifies the disruption of normal function. DSM-V (an abbreviation for the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition) not only supports diagnosis, but also enables the clinician to grade and classify the diagnosis of depression (Keefe & DeRubeis, 2016).
Depression is caused by a number of factors, most of which involve interactions between the genotype of the affected individual with environmental factors. This means that tying down the absolute cause of the condition is difficult and thus a constellation of causes are considered rather than a single cause. The main causes of depression are grief (due to either death or loss of source of income) and substance abuse. Moreover, it is better to describe the risk factors rather than the causes as this facilitates the management of the condition. The main risk factors for depression are genetic predisposition and a history of substance abuse (Keefe & DeRubeis, 2016).
There are various modalities that define the medical treatment of depression, with the main modalities being pharmacotherapy, natural alternatives, psychotherapy and electroconvulsive therapy (Keefe & DeRubeis, 2016). The paper focuses on the first two modalities of treatment.
Pharmacotherapy
Depression is managed by the groups of medications described hereafter. The physiological basis of depression is that there are low levels of neurotransmitters in the brain, and thus signal transmission is either dampened or disrupted. The first class of anti-depressants is the monoamine oxidase inhibitors (MAOIs) which inhibit the catalysis of the oxidative deamination process of intracellular monoamines including serotonin, epinephrine and norepinephrine. The main MAOIS are Isoniazid and Iproniazid. The other non-selective MAOIs include Phenelzine, Tranylcypromine, and Isocarboxazid. The most effective selective MAOI is Selegiline, which is classified as a MAO-B inhibitor (Robertson et al., 2015).
The second class of antidepressants is the tricyclic anti-depressant medications (TCAs). Imipramine is the most renowned drug in this category. The other TCAs in the market include Amitriptyline, Desipramine, Doxepin, Nortriptyline, Protriptyline, and Trimipramine. Its mode of action involves inhibition of serotonoin re-uptake thus increasing its concentration at the synapse thus facilitating signal transmission. The third class of antidepressant medications is the tetracyclic antidepressants (TECAs) which includes Mirtazapine, and whose mode of action is similar to those of TCAs (Robertson et al., 2015).
The forth class of antidepressant medications is the selective serotonin reuptake inhibitors (SSRIs) which works by inhibiting the activity of the serotonin reuptake transporter proteins thus increasing the concentration of serotonin in the synapse thus facilitating signal transmission. The main SSRIs include citalopram, dapoxetine , escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, zimelidine, and indalpine (Robertson et al., 2015).
The fifth class of antidepressant medications is the serotonin-norepinephrine reuptake inhibitors (SNRIs) whose mode of action is the same as that of SSRIs, but are more efficacious than SSRIs. The main drugs in this class are Venlafaxine and Duloxetine. Finally, the last class of antidepressant medications is the norepinephrine-dopamine reuptake inhibitors (NDRIs) whose mode of action is similar to that of both SNRIs and SSRIs, but it works more by inhibiting dopamine. Bupropion belongs to this class of drugs (Robertson et al., 2015).
Side-Effects of Antidepressant Medications
The mono-amine oxidase inhibitors are associated with the side-effects described hereafter. The four major and most-discernible side effects are decreased sexual function, weight gain, fatigue, and low blood pressure. Fatigue and low blood pressure do diminish the ability of the affected person to perform his daily tasks, thus leading to a disruption in normal activities. Weight gain is considered inappropriate, especially for young women who are on diet or whose depression can be linked to their inability to slim down their bodies (Robertson et al., 2015). In such a case, the medication provided not only treats the condition, but serves to worsen the situation by promoting weight gain thus further worsening the self-image of the affected female and hence plunging her deeper into depression. Decreased sexual function is considered inappropriate for young couples who are trying to conceive, and most are likely to discontinue the medication for this reason.
The other side effects of MAOIs are constipation, nausea and diarrhea. These three do affect the normal functioning of the gastrointestinal system and may thus lead to reduced absorption of nutrients thus building up a nutrient imbalance in the body of the patient. This is worsened by constipation which is usually associated with a reduced appetite for food, and thus nutrient imbalance is not only sustained, but further worsened. Diarrhea does cause fluid imbalance in the body, and this is associated with metabolic changes, especially with regards to the ionic balance in the plasma. The type of diarrhea usually associated with MAOIs is the fluid loss type which creates the following forms of ionic imbalance; hypokalemia and hyponatremia. This ionic imbalance affects the functions of the cardiovascular system by lowering the heart rate as well as reducing the strength of the contraction of the ventricles during systole, thus leading to a weak heart pumping blood at low pressure into the systemic circulation which explains the low blood pressure associated with use of MAOIs (Robertson et al., 2015).
MAOIs also cause dizziness, sleep disturbances and light-headedness. This is caused by changes in metabolite concentrations in the brain which affects the functions of the brain, with some of the metabolites acting on the limbic system to create a low degree of sustained arousal which causes insomnia as the affected person cannot fall asleep while he or she is still aroused. This explains the insomnia associated with MAOIs. Additionally, MAOIs also cause headache and blurred visions. This are attributed to metabolic changes in the brain which affect not only neurotransmission (which interferes with the optic pathway hence the blurred vision), but also affects blood circulation around the brain hence the headaches (Robertson et al., 2015).
The other side-effects of MAOIs are reduced urine output, increased sweating and muscle twitching. Reduced urine output is indicative of ionic imbalance in the plasma which is also associated with muscle twitching as muscle cells are sensitive to the ion concentrations in plasma. Ionic imbalance in plasma affects the function of muscle cells and this leads to the weakness, shakiness and restlessness usually associated with use of MAOIs. Increase in rate of sweating is related to persistent stimulation of the sweat glands. Moreover, increased sweating is also caused by increased muscle activity which is triggered by the plasma ionic imbalance that is caused by MAOIs (Robertson et al., 2015).
The non-selective nature of most MAOIs means that they inhibit the function of MAO-A, and this results in inhibition of tyramine metabolism thus leading to a high tyramine concentration in the blood. This high concentration causes a hypertensive crisis, and this is the cause of the cheese effect associated with use of MAOIs. The cheese effect refers to the rapid rise in blood pressure after a patient, under MAOIs regimen, consumes cheese; and this is caused by the high tyramine concentrations in blood. For this reason, patients using MAOIs are placed on a restricted or controlled; and are also advised to avoid foods which contain high amounts of tyramine such as avocados, cheese, wine, and bananas. The physiological basis of the hypertensive crisis is described hereafter. Tyramine displaces norepinephrine from its storage vesicles thus increasing the norepinephrine concentrations in synaptic and neuromuscular junctions. An increase in plasma concentration of tyramine causes a rapid rise in norepinephrine concentrations in synaptic and neuromuscular junctions. Norepinephrine causes constriction of blood vessels thus leading a rise in blood pressure; and if its concentration is high, then more blood vessels are constricted and this leads to a hypertensive crisis (Robertson et al., 2015). It is for this reason that the selective MAOI, selegiline was introduced as it does not inhibit the functions of MAO-A thus does not affect tyramine metabolism, and consequently does not cause a hypertensive crisis.
Additionally, MAOIs also participate in adverse drug-drug interactions with specific categories of drugs including serotonin-reuptake inhibitors which results in the serotonin syndrome. The serotonin syndrome is characterized by seizures, muscle rigidity, and high fevers. For this reason, MAOIs must not be administered alongside SSRIs. Additionally, pain medications, especially meperidine and tramadol, must not be administered alongside MAOIs as the resulting drug-drug interactions cause muscle rigidity and fever. Serotonin syndrome also occurs when MAOIs are administered alongside the herbal supplement, St John’s wort, which is usually used as a weight loss supplements (Robertson et al., 2015).
One of the hypotheses used to describe the physiological basis of depression is the receptor sensitivity hypothesis which stipulates that up-regulation and super-sensitivity of the post-synaptic receptors, especially the alpha-1 serotonin receptors, do cause depression as studies have shown that patients who have depression or who have suicidal thoughts tend to have above-normal populations of alpha-1 serotonin receptors. One of the ways in which TCAs act to reduce depression is by down-regulating the expression of post-synaptic receptors. However, they are non-selective on the type of receptors that are targeted for down-regulation and this leads to down-regulation of all isoforms of serotonin receptors thus resulting in weight gain and sedation. Sedation is particularly inappropriate if the TCAs are administered to a person so as to enable him or her to return back to work and function normally (Robertson et al., 2015). This is more acute for a machinist who may suffer serious bodily harm if he or she falls asleep when operating machines with movable or rotating parts such as a drilling machine or a lathe machine.
Among the TCAs, Imipramine proved effective in the management of severe depression but it also causes mania or hypomania. Nonetheless, its active metabolite, desipramine proved to be effective in management of both resistant depression and neuropathic pain. Nonetheless, TCAs are non-selective in their antagonism of post-synaptic receptors and these results in the side effects described hereafter. Antagonism of the muscarinic receptors, especially the Muscarinic M1 post-synaptic receptors causes an inhibition of cholinergic activities in the affected cells and tissues, and these results in a dry mouth, blurring of vision, retention of urine, constipation, and even impotence. Antagonism of the alpha adrenergic receptors causes postural hypotension, which manifests itself as orthostatic hypotension among people who stand for long periods of time. Unmanaged and sustained postural hypotension leads to the development of edema in the ankle region and feet of the affected individual and this may progress to the development of myxedema which is quite difficult to reverse because additional tissue has been added in the extremities (Robertson et al., 2015).
In the heart, TCAs act on the cardiac cells and reduces their membrane potential thus leading to the development of arrhythmias. The cardiotoxicity of TCAs manifests itself as aberrant readings in electrocardiographs (ECG). Moreover it causes slow cardiac conduction, and this has been attributed to the leakage of lactase dehydrogenase (LDH) enzyme from the intracellular compartment into the extracellular compartment (Robertson et al., 2015). This implies that use of TCA leads to a rise of LDH concentration in the plasma.
In the neuronal cells, especially the neurons located in the brain, TCAs act on their membrane, and consequently reduces their membrane potential thus causing seizures. This explains the seizures which are associated with use of TCAs. The side-effects of tetracyclic antidepressants are the same as those of tricyclic antidepressants because they both use the same mode of actions and act on the same receptors and chemical compounds (Robertson et al., 2015).
Among the SSRIs, indalpine was shown to cause fetal neutropenia, and it can thus not be used to treat depression in pregnant mothers. Its congener, Zimelidine causes neurological problems such as the Guillain-Barre syndrome. SSRIs act by binding to presynaptic serotonin reuptake transporters thus increasing the concentration of serotonin in the synaptic space, and such a high concentration of serotonin causes a down-regulation of serotonin receptors on the post-synaptic cells. In the long term, this can lead to a degree of desensitization of the post-synaptic cell to serotonin. Thus, its side effects also relate to desensitivity of the post-synaptic cell to serotonin (Robertson et al., 2015).
The main side effects associated with the use of SSRIs are apathy, anhedonia, nausea, somnolence, vomiting, dizziness, headache, fatigue and suicidal thoughts. SSRIs also interfere with the sexual functions of a person, and this lead to discernible changes in the person’s sexual behavior. This is due to overstimulation of the serotonin-2 receptors which causes a reduction in dopamine release hence low libido and erectile dysfunction (Robertson et al., 2015).
Increase in serotonin concentration in the brain is associated with strange dreams; with the affected person sometimes have extremely vivid nightmares. SSRIs also cause bruxism which is the involuntary grinding of teeth that result from inappropriate stimulation of the neurons innervating the jaw muscles (Robertson et al., 2015).
Usually, the side effects of SSRIs tend to disappear with the first four weeks after a person has started to use them, and this is thought to be adaptation phase where the body of the person is adapting to the introduction of a xenobiotic (SSRIs) as well as adapting to the changes caused by the drugs. Additionally, discontinuation of SSRIs can cause the SSRI cessation syndrome which is characterized by brain zaps and sexual dysfunction (Robertson et al., 2015).
The side-effects of SNRIs are the same as those of SSRIs because they both use the same mode of actions and act on the same receptors and chemical compounds. Nonetheless, SNRIs, especially venlafaxine has been shown to increase the risk of suicide by a factor of 1.6 as compared to SSRIs such as fluoxetine.
NDRIs have the same side effects as SNRIs and SSRIs. However, Bupropion is a more potent inhibitor of dopamine and is also antagonistic on the anα3-β4 nicotinic receptor. This causes the drug to lower the seizure threshold in patients who use it, and this has results in seizures (Robertson et al., 2015).
Therefore, it is evident that the antidepressant drugs have known side-effects which are unacceptable, especially in the long term, because they seriously harm the well-being of the person using them. Moreover, there are other alternatives to antidepressants, and thus it is prudent that the alternatives be used accordingly.
Natural Alternatives
The main natural alternatives to antidepressants are herbal alternatives, exercises, pet therapy and exposure to the sun. They are discussed hereafter. The main natural and herbal alternatives to antidepressant medications, which have also been reviewed by the National Institutes of Health, and found efficacious, are the St. John worts, omega 3 fatty acids, saffron, folate, zinc and S-adenosylmethionine (SAM-e). St. John worts increase the plasma concentration of serotonin, and this is indicative of the fact that serotonin concentration within the synaptic space is also increased. Nonetheless, St. John worts interacts with lots of drugs including blood thinners and contraceptive pills, and is thus contra-indicated in most instances (Solomon & Adams, 2015).
Omega 3 fatty acids are found in trout, salmon and sardines. It increases the concentration of serotonin in the brain thus managing depression. Saffron is derived from crocus and is effective in the management of mild forms of depression. SAM-e is an analogue of the S- adenosylmethionine that is synthesized de-novo in the human body. SAM-e is effective in the management of mild to moderate forms of depression. Folate and Zinc are two micronutrients that have been shown to improve mental functions as well as reduce the severity of depression. The other management alternatives such as exercises, massage therapy, pet therapy and exposure to the sun serve to elicit the body to increase its production of endorphins and serotonin which ultimately improve the mood of the affected person (Solomon & Adams, 2015).
Thus, it is evident that the natural alternatives to antidepressant medications do not have serious side effects. Nonetheless, their potency and efficacy in managing depression is low, and they are thus more useful in the management of mild to moderate depression.
Conclusion
Depression is an affective disorder which manifests itself with mood changes and a feeling of low self-worth. There is a need to treat depression so as restore the normal functioning of a person as well as avert suicide. The six main classes of antidepressant drugs are MAOIs, TCAs, TECAs, SSRIs, SNRIs, and the NDRIs. These antidepressant drugs have known side-effects which are unacceptable, especially in the long term, because they seriously harm the well-being of the person using them. Moreover, there are other alternatives to antidepressants, with the main alternatives being herbal alternatives, natural supplements, exercises, pet therapy and exposure to the sun. These alternatives have minimal to no side-effects. Thus, antidepressant medications do have unacceptable side-effects which do harm the overall well-being of people suffering from depression hence necessitating the use of the other alternatives to antidepressants.
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References
Keefe, J. R., & DeRubeis, R. J. (2016). A Critique of Theoretical Models of Depression:
            Commonalties and Distinctive Features. Treating Depression: MCT, CBT, and Third-
            Wave Therapies, 242-261.
Robertson, D. B., Maibach, H. I., Katzung, B., & Trevor, A. (2015). Basic and Clinical
            Pharmacology.
Solomon, D., & Adams, J. (2015). The use of complementary and alternative medicine in adults
            with depressive disorders. A critical integrative review.  Journal of Affective
            Disorders179, 101-113.
Stahl, S. M., & Schwartz, T. L. (2016). Stahl's Essential Psychopharmacology: Case
            Studies (Vol. 2). Cambridge University Press.

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