The Pharmacology of Antidepressant Medications

Evidence-based psychiatric treatment relies on trust between physicians and their clients to find the best solutions possible for dealing with mental illness. Clients should be receptive to medications that can improve mood and quality of life while their doctors make a medication choice based on the client’s personal history, diagnosis, and lifestyle that has the least possible or least adverse side effects.

Earlier this year, Adam Meadows, MD, one of Skyland Trail’s psychiatrists, spoke to STEP families about the pharmacology of antidepressant medications. You can listen to his presentation here.

Types of Antidepressant Medications

For someone with a mental illness like depression, taking medications to reduce their symptoms is a part of their daily lives. Today, antidepressants may even be household names thanks to more widespread marketing and advertising; mentions in popular music, movies, and media; and even dinner table conversations as families begin to talk more openly about mental health. It wasn’t long ago that psychiatric medications like antidepressants were in their infancy.

Monoamine oxidase inhibitors (MAOIs) for treatment of depression

In the 1950s, a plant called Rauwolfia serpentine, or Indian snakeroot, was used to create a medication for treating hypertension and other vascular issues. While the medication improved blood pressure, physicians also began to notice a decline in mood among its users. After some research, it was found that Reserpine decreased monoamine transportation within the brain, notably dopamine, serotonin, and norepinephrine. This finding led to the origin of the Monoamine Hypothesis for depression, suggesting that a decline in those chemicals can have a detrimental effect on mood.

Around the same time, medications called Isoniazid and Iproniazid were being used to treat and manage tuberculosis. Aside from noticeable improvements in lung functioning, patients also experienced euphoria, increased appetite, stimulation, and even improved sleep. People were improving physically and emotionally. These two medications were shown to increase levels of the monoamines that medications like Reserpine were decreasing. This led to the first categorization of antidepressant medications called monoamine oxidase inhibitors, or MAOIs.

Monoamine oxidase (MAO) is an enzyme that breaks down monoamine chemicals like serotonin, dopamine, norepinephrine, melatonin, and tyramine. In short, medications that inhibit the effectiveness or prevalence of monoamine oxidase can help treat symptoms of depression by increasing the levels of chemicals that have an uplifting effect on mood.

While there are many FDA-approved MAOI antidepressants, patients taking these medications often have to follow strict diets and avoid other common medications to avoid a buildup of tyramine. Eating foods like wine and cheese that have been aged or pickled is typically out of the question. Ingesting these tasty treats can cause fast heartbeat, dizziness, tremors, sweating, and increased blood pressure. MAOI users also have to forego other medications including antihistamines, over-the-counter cold medications, and many other medications prescribed for depression and hypertension.

Tricyclic Antidepressants (TCAs)

Originally derived from antipsychotic medications to treat schizophrenia, another antidepressant medication was created as an alternative to MAOIs. In 1959, Imipramine became the first FDA-approved tricyclic antidepressant. Tricyclics primarily affect serotonin and norepinephrine. While effects on schizophrenia were shown to be minimal, physicians again noticed improved mood in patients with depression. One of the downsides of tricyclics (also known as TCAs) however is they are not selective and they can cause side effects linked to dryness such as dry mouth, constipation, and other unwanted reactions. Pharmaceutical researchers again looked to find alternatives that might be better tolerated for users.

Selective serotonin reuptake inhibitors (SSRIs) for treatment of depression

In the 1960s, pharmaceutical company Eli Lilly took the lead on serotonin research. By 1974, they became the first to publish a report on a selective serotonin reuptake inhibitor drug called LY110140, also called Fluoxetine. In 1987 Fluoxetine was FDA approved and came to market in 1988 as Prozac, which started the era of receptor selective medications. Prozac soon became part of popular culture in the 1990s, penetrating movies, television, books, and media as it began to rise in popularity. Today it is still one of the most recognizable brand name SSRIs on the market. Other FDA-approved SSRIs include medications like Citalopram (Celexa), Escitalopram (Lexapro), Paroxetine (Paxil), Sertraline (Zoloft), and Fluvoxamine (Luvox).

In 2004 the FDA issued a warning that SSRIs increase suicidality in adolescents and young adults, which led to a decrease in prescribing SSRIs to teens. Although research didn’t conclude a causal relationship between SSRIs and suicidality, physicians exercise caution in prescribing to adolescent and young adult patients to first test their affinity and reactions. Some SSRIs may also induce sexual dysfunction for both genders such as lowered libido. The higher the dosage of SSRIs, the more pronounced these side effects may become. SSRIs also can cause hyponatremia, or a low amount of sodium, which may lead to altered thinking or confusion, usually in patients with other medical conditions. Osteopenia and Osteoporosis are other side effects of SSRIs which can affect bone density with long-term use. In older individuals, GI bleeding may also occur, particularly if patients are taking blood-thinning medications or have experienced a previous GI bleed.

Serotonin norepinephrine reuptake inhibitors (SNRIs) for treatment of depression

Efforts to offer alternatives to existing antidepressant medications continued. The next class of medications introduced was serotonin norepinephrine reuptake inhibitors or SNRIs. Unlike TCAs, SNRIs tend to be more tolerable for patients. Some examples include Duloxetine (Cymbalta), Venlafaxine (Effexor), Desvenlafaxine (Pristiq), and Levomilnacipran (Fetzima).

Atypical Medications for Depression

Another common antidepressant medication is Bupropion, more commonly known by the brand name Wellbutrin. Bupropion is an NDRI, which means it affects dopamine and norepinephrine reuptake. Typically, NDRIs create stimulant-like symptoms, and they are commonly used as an add-on to SSRI’s to enhance the overall antidepressant response, or sometimes reduce SSRI-related sexual dysfunction. Many people also use Bupropion, under the brand name Zyban, as a medication to assist with smoking cessation.

Another common atypical antidepressant medication is Mirtazapine, branded as Remeron, which came out in the mid-1990s and affects norepinephrine and serotonin release indirectly. Just like many other medications, prescribers commonly add Mirtazapine to other antidepressants to improve the overall treatment response, though sedation and increased appetite are side effects that may occur. Another atypical antidepressant, Vilazodone, branded Viibryd, affects serotonin exclusively and must be taken with a meal in order to be fully absorbed. On an empty stomach, it is more likely to cause side effects like upset stomach, bloating, and other gastrointestinal discomfort.

In 2013 the FDA approved a drug called Vortioxetine under the brand name Trintellix. Trintellix is marked as a significant milestone for antidepressant medications because it has been shown to improve cognition, namely processing speed, in patients with depression.

Ketamine Treatment for Depression

Initially introduced as a short-term anesthetic in the 1970s for soldiers in Vietnam, ketamine was used as a proof of concept for depression in 2000. Clinical evidence suggests that glutamate dysfunction is implicated in patients with major depressive disorder. Ketamine’s response time and delivery method is drastically different than many other medications, taking only minutes or hours to reduce symptoms while other medications may take up to several weeks. Ketamine is generating a similar amount of headlines in today’s media because of its risk for misuse and abuse. Ketamine usually is delivered intravenously at medical clinics. However, in 2019 the FDA approved a nasal spray version of ketamine that must be administered under a doctor’s supervision, called esketamine (or brand name Spravato), to treat depression in certain groups of patients.

Sequence Treatment Alternatives to Relieve Depression Study (STAR*D)

In 2006, the National Institute of Mental Health (NIMH) published the largest antidepressant medications study to date. The study, which included more than 4,000 patients diagnosed with major depressive disorder over a seven year period, looked at how remission levels of depressive symptoms could be achieved through a combination of medication treatment and psychotherapy. Unlike many other studies that look for a merely a reduction of depressive symptoms, the STAR*D Trial went a step further and measured individuals who achieved full remission of symptoms. Through each level of the trial, patients had the opportunity to choose between adding on a medication to an SSRI, adding psychotherapy, or switching to a different medication altogether to try to find the best treatment solution. Having such a large, federally funded study gave both physicians and patients more data to be able to determine effective treatment strategies, and understand how different people react to different medications and combinations of antidepressants over both short and long periods of time. 

Selecting the Right Medications for Depression

The four Ds of prescribing medications help psychiatrists find the best solution for a patient.

Psychiatrists use many tools to select the best antidepressant medication strategy for patients, often following the four Ds of prescribing medications: the right drug, the right dose, in the right delivery method, and for the right duration of time. This can vary among individuals based on personal history. It typically takes at least two weeks for patients to begin to see improvement. The lag between action and results contributes to medication adherence problems. Patients don’t feel results fast enough, so they stop taking their medications.

Personal history is often the first step a doctor takes when considering which medications to prescribe. What has this person been prescribed before? What worked well about the medication, and what didn’t work well? Family history, first-degree especially such as biological parents and siblings, are good indicators of how patients will react to medications. Medical history is also important, particularly with drug interactions that may worsen side-effects or create other issues.

Another factor is the out-of-pocket medication costs and insurance coverage. Patients struggle to be adhere to medications that they cannot afford long-term.

Besides being affordable, targeting specific symptoms and understanding the side-effects of medications are also very important. Does a medication really hone in on symptoms that patients struggle with like sleep or insomnia? What are the deal-breakers in terms of side-effects? People have different tolerances for discomfort. Often the desired goals of medication include improving function and quality of life.

Additionally, the way in which a drug is administered should be considered as well. A person that struggles with needles likely won’t find IV or intra-muscular injections to be a sustainable form of medication. How realistic is a medication given a person’s individual lifestyle or life stage? For example, a college student with a hectic or unpredictable schedule may have more issues with medication management while an older adult may be more-suited to use a medication that requires daily dosing.

Research is ongoing in the potential effectiveness of pharmacogenetic testing, a process of studying the genes of an individual to predict the effectiveness of certain medications or chemicals and may be a useful tool in a doctor’s approach to combatting depression.

It’s important for psychiatrists and other physicians to consider and balance all of these factors when determining the right medication choice.

Depression medication as part of a holistic approach to mental wellness

At Skyland Trail, we don’t believe in a one-size fits all method of treatment. The treatment team uses evidence-based methods to address a client’s mental illness including a combination of medications, group therapy, individual therapy, unique expressive therapies like art and music, life skills, and independence coaching. The Glenn Family Wellness Clinic also offers transcranial magnetic stimulation services for individuals who are struggling with treatment-resistant depression.