The Development of Fluoxetine for Major Depressive Disorders - Essay Example

?Severe desperation, downcast with feelings of loss and meagreness are crucial in defining the mental disturbance that is depression. Depression is acommon occurrence in almost all people since it is a normal response to many of the stresses in life. As such, depression is regarded as abnormal when it exceeds the magnitude of the trigger event and extends beyond the point regarded point of recovery. Among the situations that most often precipitate depression are failures at school or work, loss of a loved one, illness, old age among others. In addition to emotional symptoms that are characterised by mood swings, there are cognitive, motivational and physical symptoms. Sadness and dejection are the most salient symptoms in depression, which are accompanied by loss of gratification or pleasure in life. Cognitive symptoms consist primarily of negative thoughts and loss self-esteem where one blames himself for their failures. A person suffering from depression tends to be passive and have difficulty initiating activities since their motivation is at low ebb. Physical symptoms of depression include loss of appetite, sleep disturbances, fatigue, and loss of energy among others (Revarta n.d). An individual need not to have all of the above symptoms to be diagnosed as depressed, but the more symptoms one has and the more intense they are, the more certain an individual can be suffering from depression. Depression has been linked to a wide variety of factors that are believed to spark the onset of depression. Genetics, environmental factors, trauma and stress are among the key factors that are regarded as the initiators of depression. However, whatever the trigger may be, depression is associated with the physiological and chemical changes in the brain. This is more so due to the imbalances associated neurotransmitters, which are charged with the task of carrying signals between the nerves. This is in line with the proposal highlighted by the monoamine hypothesis. This hypothesis has its origins in the 1950s where the role of antihypertensive medication in causing depression was queried following depleted levels of neurotransmitters in the brain. The classical theory in relation to the biological aetiology of depression indicates that the condition is due to a deficiency of monoamine neurotransmitters (Stahl 2008 p.480). The monoamines are the prime focus owing to the nature of their synthesis from amino acid precursor that is tryptophan for serotonin and tyrosine for norepinephrine, epinephrine and dopamine. Researchers debated on the hierarchy of importance among the neurotransmitters namely; norepinephrine, serotonin and dopamine and as such, they could not focus on the biology of depression. Presently, the monoamine theory suggests that the entire trimonoaminergic neurotransmitter system may be malfunctioning within various brain circuits and the different neurotransmitters involved create the variety of symptoms in patients (Hall 1998, p.1). The monoamine hypothesis suggests that at least some depressions occur because of a complete or relative deficiency of neurotransmitters, and in particular norepinephrine at key receptor in the brain. The conceptualisation of this theory was based on observations made on particular drugs, which suppressed these neurotransmitters to induce depression. Further observations indicated that a majority of effective antidepressants acted by boosting one or more of the three monoamine neurotransmitters, which is evidenced by the mode of action of most antidepressants on the current market. Modern antidepressants work by blocking the re-uptake of monoamines from the nerve synapses, which affords the monoamines a longer stay with the synapse. This prolongs the signal transfer between nerve cells a characteristic exhibited by a majority of selective serotonin reuptake inhibitors. Despite the existing findings, direct evidence for the monoamine hypothesis is largely lacking, which has sparked off criticism on the theory. It has been argued that some antidepressants work efficiently despite not following the monoamine pathway. Similarly, some studies indicate that some patients whose monoamines were depleted did not appear depressed neither did the depletion worsen depression in depressed patients. Owing to the underlying shortcomings of the monoamine hypothesis of depression, the focus shifted from the neurotransmitters to the receptors, which follows acknowledgment that the neurochemical basis of depression is complex and is not influenced by any specific deficit (Placek n.d., p.34). Antidepressant drugs are as popular as they are controversial which is evidenced by the number of people under this medication owing to various mental and psychological conditions that they suffer. Researchers came across the first antidepressant by chance while seeking treatment for schizophrenia in the 1950s. The scientists discovered a drug that altered the balance of neurotransmitters within the brain to control the mood of the patient. However, they realised that the drug only made the patient’s condition worse and the drug was best suited for patients suffering from depression. The drug was marketed as tofranil and was followed by an upsurge other similar drugs as companies rushed to take advantage of the new market (Healy 2004, p.33). This marked the discovery and emergence of tricyclic antidepressants and the monoamine oxidase inhibitors to provide effective treatment options for depression. The formulation and manufacture of antidepressant drugs was based on the monoamine hypothesis of depression, which aimed at balancing the neurotransmitters in the brain to alter behaviour. In the 1970s, studies illustrated the role of serotonin in depression and a hypothesis was put forth that formed the basis of the next generation antidepressant drugs. This hypothesis suggested that by elevating the neurotransmission of serotonin would prompt an antidepressant response. As a result, research cemented the way for the discovery and manufacture of serotonin reuptake antidepressant, which was consequently, approved by the Food and Drug Administration (FDA) agency for the treatment of depression. Adapted from http://www.reverta.com/depression/ Fluoxetine is a selective serotonin reuptake inhibitor that is widely marketed as Prozac and is known to be the most prescribed antidepressant drug (Aronson 2008, p.57).Prozac works by increasing the levels of serotonin in the brain, which then alters the patient’s mood, appetite, and general behaviour. The synthesis of the drug was completed in 1972following a quest that was commissioned 2 years earlier to develop a better antidepressant (Landau et al 1999, p., 219). Clinical trials in animals for fluoxetine began in 1976 where studies were done and completed. An assumption was made based on the side effects of other drugs with similar composition and as such, the researchers filled an application of investigational new drug under the FDA. Clinical investigations indicated that fluoxetine doses as high as 90mg were well tolerated by human volunteers and previous intolerance seen in rats was inhibited (Wong et al 2005, p.770). The trials also indicated that fluoxetine effectively bound selectively to the desired receptors to inhibit serotonin uptake. This successfully concluded phase I clinical safety studies initiating phase II clinical trials, which were faced with financial challenges and an influx of volunteers. However, during the trials, fluoxetine was illustrated to be an effective remedy when treating patients with depression. These findings were reaffirmed during phase III clinical trials when fluoxetine was shown to be effective in the treatment of major depression with minor side effects than the tricyclic antidepressants. The drug was introduced to the US market in 1988 where its popularity grew to become the most prescribed drug in 1990. The Food and Drug Administration agency approved fluoxetine for a number of indications, which include but not limited to major depressive disorder, obsessive-compulsive disorder, bulimia nervosa, panic disorder and premenstrual dysphoric disorder. Other off label and investigational uses of Prozac include smoking cessation, chronic pain syndromes, and anxiety disorders in children, attention-deficit hyperactivity disorder and Tourette's syndrome. In addition, fluoxetine has indicated activity in patients with severe migraine headaches where the drug is known to reduce their frequency and severity. Similarly, chronic pain associated with fibromyalgia has been reported as relieved by moderate doses of Prozac. The drug has also been demonstrated to increase the latent period associated with ejaculation, which is of benefit to patients suffering from premature ejaculation. The metabolised form of fluoxetine, norfluoxetine, is thought to be the active ingredient in the antidepressant drug. The drug is well absorbed in the gastrointestinal tract following oral administration where the bioavailability is estimated at 60-80%. Availability is believed to be at its peak in plasma within 4-8 hours of oral administration of a regular dosage. The antidepressant effect of fluoxetine is linked to the selective inhibition of serotonin reuptake, which blocks the reuptake pump of the neuronal membrane (eMedExpert, 2012). In essence, fluoxetine terminates the action of the sodium-dependent serotonin transporter through the synaptic terminals, which enhances the action serotonin on the 5HT1Aauto receptors to produce antagonist effects (DrugBank, n.d). Studies on fluoxetine indicate that the plasma levels of norepinephrine, epinephrine and dopamine increase significantly following treatment with Prozac. The half-life of a lone dose of Prozac is 2-3 days, which is evidenced by the slow clearance of the drug from the body. In the liver, fluoxetine is converted into norfluoxetine, which is also a serotonin inhibitor, but with an extended half-life. Consequently, the extended half-lives may see the active ingredients take months to be eliminated from the body (Fluoxetine Hydrochloride n.d., p.3). This explains the emergence of withdrawal symptoms following an abrupt discontinuation of prescription. The symptoms include dysphoric mood, irritability, fatigue, sensory disturbances, anxiety, confusion, headaches, nausea and vomiting among others. Fluoxetine has been associated with numerous advantages over other antidepressant drugs and is the drug of choice for persons with hypersomnia and psychomotor retardation. The drug is advocated for patients who have a low compliant rate with other antidepressants since missing a dose does not create problems. This is attributed to slow rate of drug elimination by body due its extended half-life. It is also the only drug in its class approved by the food and drug administration agency for prescription to children 8 years of age and above. In addition, patients under Prozac have a lowed potential of gaining weigh compared to other drugs (“The SSRI Issues” n.d., p.22). Adapted from http://www-rohan.sdsu.edu/~jmahaffy/courses/s00a/math121/lectures/deriv_exp_ln/specialf.html However, fluoxetine is not advocated for patients with concomitant anxiety, panic and agitation due to the delay action of the drug. Prozac is also regarded as a less effective drug compared to others used in treatment of depression while the probability of activating adverse effects is relatively high. For instance, Prozac is known to alter the blood glucose levels in patients with known cases of diabetes. The long half-life proves to be a hindrance when switching to another antidepressant and produces undesired effects due to drug interactions. In addition, patients experience changes in their sleeping patterns as well as a reduced sexual drive. References Placek, K. n.d. Prenatal Fluoxetine Exposure: Mitigation of Affective Behavioural Deficits through Neonatal Tactile Stimulation. [Online]. Available from http://www.smcm.edu/psyc/_assets/documents/SMP/Showcase/1112-KPlacek.pdf [Accessed 13/03/2013] Healy, D. 2004. Let Them Eat Prozac: The Unhealthy Relationship Between the Pharmaceutical Industry and Depression. New York: NYU Press. Wong, D. Perry, K and Bymaster, F 2005.The Discovery of Fluoxetine Hydrochloride (Prozac). [Online]. Available from. http://journals2005.pasteur.ac.ir/NR/4(9)/764.pdf [Accessed 13/03/2013] Fluoxetine Hydrochloride. [Online]. Available from. http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/018936s064lbl.pdf [Accessed 13/03/2013] Hall, R 1998. Theories of Depression. [Online]. Available from. http://web.mst.edu/~rhall/neuroscience/07_disorders/depression_theory.pdf [Accessed 13/03/2013] The SSRI Issues. n.d. [Online]. 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