Of all mental disorders, depression is the most common, and up to 300 million persons suffer from the ailment around the world, according to the WHO (“Depression”). Symptoms of the disease vary depending on the condition and include loss of interest in the environment and usual activities, consistently low mood, reduced or excessive sleep and appetite, and, in severe cases, suicidal thoughts. However, numerous drugs to manage depression have been developed. The drugs have evolved from iproniazid, isoniazid, and imipramine used in the 1950s (Lopez-Munoz and Alamo 1563), to current medication such as inhibitors that prevent the reuptake of serotonin and norepinephrine.
Depression: A Historical Perspective
In the past, the society recognized depression as possession by demons rather than as an illness. Early Mesopotamian texts identified the disease as “Melancholia,” and priests would usually exorcize the “demons” as a form of treatment. Physicians of the time only concerned themselves with conditions that had physical symptoms. The same applied to other ancient civilizations, such as Egyptians, Greeks, and Romans. Later, physicians identified the ailment as one which was transferred at birth and defined it as an “unchangeable weakness of temperament” (Nemade and Patricelli). The consequences of the view that depression was inherited caused patients to be shunned and separated from the society in specialized institutions. Those who could not afford to be in mental hospitals became homeless and roamed the streets.
At first, depression was treated through barely effective therapies. For example, during water immersion, physicians kept patients underwater for long periods of time without drowning them. Some practitioners used spinning on special stools to rearrange the contents of the brain. Later came electroshock therapy, which was introduced by Benjamin Franklin, and other modes of management, such as particular nutrition regiments, horse riding, and induced vomiting (Nemade and Patricelli). However, none of the above, except some forms of electroconvulsive therapy, is currently considered beneficial.
The Evolution of Antidepressants: Monoamine Oxidase Inhibitors (MAOIs) and TRAs
After doctors found that some medications to treat tuberculosis also worked on patients diagnosed with depression, antidepressants were introduced. After the 1952 discovery, drugs became the method of choice for treating depression. The first antidepressant was isoniazid. Doctors found that the drug enhanced the moods of patients, and this became the focal point for the transition of psychiatry from a psychoanalysis viewpoint to the notion that mental illness has a biological basis. The drug, which belongs to the group of hydrazine compounds, was synthesized by scientists from Prague in the 1870’s (Ramachandraih et al. 180). It worked via inhibiting the breakdown of norepinephrine by the monoamine oxidase (MAO) enzyme. Instead of sedating patients, isoniazid made them more active and improved their moods (Maxwell and Eckhardt 144). However, in the early 1960s, scientists found related instances of hepatitis, and this side effect prompted the withdrawal of the drug from the market.
Afterward, less hepatotoxic drugs such as phenelzine and isocarboxazid were developed. Phenelzine is also a monoamine oxidase inhibitor (MAOI). Though its utility in psychiatry first ensued in the 1960s, phenelzine is still widely used in modern times. It functions via the increase of certain chemicals in the brain and treats indicators of depression such as mood swings, chronic anxiety, and hypochondria (the apprehension that one’s physical health may suffer). Doctors noticed that their patients had improved appetites, were more social and vigorous, and could sleep better (Ramachandraih et al. 181). However, phenelzine should not be used in cases of chronic or manic depression, and physicians should use the drug only if other medications are not effective in eliminating symptoms (National Center for Biotechnology Information). Like isoniazid, some studies have linked phenelzine to instances of liver failure in patients, some of which were fatal, albeit on a reduced scale (Ramachandraih et al. 181). For example, a 59-year-old male developed jaundice two months after starting phenelzine and later progressed to severe and prolonged liver injury (National Institutes of Health).
Similarly, isocarboxazid also functions as a MAOI. Its use ensued around the same time as phenelzine, nialamide, and etryptamine, among others, which became frequently prescribed antidepressants. Unfortunately, psychiatrists found that most MAOIs resulted in hypertension and hepatoxicity. In hypertensive cases, patients who were found to have ingested items with high levels of tyramine exhibited the “cheese effect,” which caused elevated blood pressure, sweating, and increased heart rates. Such dangerous side effects prompted the development of selective inhibitors. MAOIs currently in use were made safe by the creation of selective MAOIs like moclobemide. The drug was found to have the same effect on patients as SSRIs and was generally well tolerated by patients.
Meanwhile, psychiatrists utilized imipramine (a tricyclic antidepressant) on their patients and noted an immediate improvement. While scientists carried out extensive research and had the same conclusions, critiques described imipramine as only relieving symptoms and not providing a cure. Nevertheless, the drug’s use grew as its success rate was high (Ramachandraih et al. 182). Its success prompted the synthesis of other tricyclic antidepressants, such as amitriptyline, trimipramine, and desipramine; and tetracyclics like mianserin.
The Development of Selective Serotonin Reuptake Inhibitors (SSRIs) and SNRIs
During research, scientists recognized that a common factor caused the success of MAOIs, tricyclics, and tetracyclics: the enhancement of serotonin and catecholamines levels in the brain (Ramachandraih et al. 184). As a result, SSRIs became the new norm in the management of depression. Unlike MAOIs, which act as inhibitors, SSRIs increase serotonin, a neurotransmitter, by hindering its reuptake in the brain. SSRIs include paroxetine, escitalopram, and sertraline. They can also be used in the treatment of other mental conditions such as posttraumatic stress disorder (PTSD), bulimia, anxiety, and compulsive disorders. Like all drugs, SSRIs have side effects, which include queasiness, lack of sleep, and lethargy. However, they lack fatal disadvantages such as the hepatotoxicity seen in MAOIs.
In the era of rational design of drugs, it has become possible to make SSRIs selective due to the discovery of psychotropics (drugs that treat psychological symptoms) that affect specific biomolecules. Specifically, SSRIs only affect serotonin levels. This scientific innovation was crucial as it could prevent the unwanted side effects of earlier drugs where medication could act on many sites (Ramachandraih et al. 184). In addition, the extensive use of SSRIs and SNRIs is attributable to the few short and long-term side effects they produce.
Serotonin-norepinephrine reuptake inhibitors (SNRIs) work in a similar method as SSRIs except for inhibiting the uptake of norepinephrine alongside serotonin. Other than managing depression, this class of drugs can also treat anxiety disorders and chronic pain. They are also particularly helpful in the management of a depressive patient who has chronic pain. SNRIs approved for use by the Food and Drug Administration (FDA) include Duloxetine and Venlafaxine (Hillhouse and Porter 5). While some individuals may not have side effects when prescribed the drugs, typical results of SNRIs are similar to those of SSRIs. Some of these medications have also been discovered to cause hypertension and hepatotoxicity in specific patients, which could be fatal. Serotonin syndrome is another potentially fatal side effect of SSRIs intake.
The most current FDA-approved drugs are levomilnacipran, vortioxetine, and vilazodone. Levomilnacipran is an addition to the SNRI class of drugs. While it prohibits both serotonin and norepinephrine reuptake, the inhibition is more useful for norepinephrine. It may cause increased blood pressure, urinary issues, and erectile dysfunction. A new SSRI drug called vilazodone, other than inhibiting serotonin reuptake, also acts as a partial agonist of the 5-HT1A receptor on presynaptic neurons (Elmaadawi et al. 28). Its adverse effects include nausea, diarrhea, headaches, and weight gain. Vortioxetine, is also an SSRI that increases dopamine and acetylcholine. It is particularly useful in depressive patients who are elderly and have cognitive deficits. The range of available antidepressants is expanding with more selective and effective drugs suitable for different purposes.
In conclusion, drugs to aid in the treatment of depression have significantly evolved during the last fifty years. From the early use of a tuberculosis drug, isoniazid, a wide range of antidepressants exists today. They include monoamine oxidase inhibitors (MAOIs), tricyclic (TRA) and tetracyclic (TeCA) antidepressants, selective serotonin reuptake inhibitors (SSRIs), and Serotonin and norepinephrine reuptake inhibitors (SNRIs). Also, medication for depression has become more selective as it acts on specific predetermined biological targets, which has reduced the instances of fatal side effects caused by non-specific pharmacological action.
“Depression.” World Health Organization, www.who.int/news-room/fact-sheets/detail/depression.
Elmaadawi, Ahmed, et al. “Prescriber’s Guide to Using 3 New Antidepressants: Vilazodone, Levomilnacipran, Vortioxetine.” Current Psychiatry, vol. 14, no. 2, Feb. 2015, pp. 28–32. www.mdedge.com/psychiatry/article/96727/depression/prescribers-guide-using-3-new-antidepressants-vilazodone.
Hillhouse, Todd M., and Joseph H. Porter. “A Brief History of the Development of Antidepressant Drugs: From Monoamines to Glutamate.” Experimental and Clinical Psychopharmacology, vol. 23, no. 1, 2015, pp. 1–21., doi:10.1037/a0038550.
Lopez-Munoz, Francisco, and Cecilio Alamo. “Monoaminergic Neurotransmission: The History of the Discovery of Antidepressants from the 1950s Until Today.” Current Pharmaceutical Design, vol. 15, no. 14, Jan. 2009, pp. 1563–1586., doi:10.2174/138161209788168001.
Maxwell, Robert, and Shohreh Eckhardt. Drug Discovery: A Casebook and Analyses. Humana Press, 1990.
Nemade, Rashmi, and Kathryn Patricelli. “Historical Understandings of Depression Continued.” Gulf Bend Center, www.gulfbend.org/poc/view_doc.php?type=doc&id=12996&cn=5.
“Phenelzine.” National Center for Biotechnology Information. PubChem Compound Database, U.S. National Library of Medicine, pubchem.ncbi.nlm.nih.gov/compound/Phenelzine#section=Top.
“Phenelzine.” National Institutes of Health, U.S. Department of Health and Human Services, livertox.nih.gov/Phenelzine.htm#top.
Ramachandraihih, Chaitrat, et al. “Antidepressants: From MAOIs to SSRIs and More.” Indian Journal of Psychiatry, vol. 53, no. 2, 2011, p. 180. doi:10.4103/0019-5545.82567.