Pharmacology

Unraveling the Enigma of SSRIs: How Do They Work, and Do They Really?

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SSRIS, or Selective Serotonin Reuptake Inhibitors, are a type of psychiatric drugs used to treat symptoms of depression and anxiety, or depressive and anxiety disorders. They are the most commonly prescribed antidepressants, and first began being used clinically in the late 1980s. The first ever SSRI, fluoxetine, was cleared for prescription usage in the United States in 1988, and paved the way for a new, much more reliable form of antidepressants. As of 2018, it is estimated that 13.2% of Americans above the age of 12 are on some form of SSRIS. The question is, what are they, really, and how do they work? 

It’s important to first understand the Serotonin Hypothesis of Depression. This hypothesis states that low levels of serotonin (a neurotransmitter related to mood, sleep, digestion, and much more) in the brain, or an inability to process serotonin correctly, is the leading cause of depression. Within this hypothesis lays the groundwork for SSRIS; the theory being that increasing serotonin in the brain lowers symptoms of depression. Therewithal, it is incredibly difficult for scientists to measure serotonin levels, as when done through bodily fluids, such as blood, urine, or cerebrospinal fluid, deficits do not appear, even when the person has been clearly diagnosed with depression. This is because neurotransmitter levels in the brain are extremely localized, and therefore not well reflected by levels throughout the rest of the body. This makes it difficult for scientists to objectively ‘prove’ the serotonin hypothesis, and as of 2022, many psychiatrists no longer accept the serotonin hypothesis, claiming there is no direct correlation between serotonin levels and depression. But, if the serotonin hypothesis is false, why are SSRIS so commonly used, and do they really work? 

Here’s what we do know. After a few doses of an SSRI, serotonin levels in the brain increase. This happens because the SSRI blocks the reabsorption (or reuptake) of serotonin into the neurons, allowing the neurotransmitter to better send messages between neurons. SSRIS are classified as selective because they only block the reabsorption of serotonin, and not of other neurotransmitters. If the SSRI works properly, the patient should see decreased symptoms of depression within the first two weeks to a month. And that’s it. That’s how they work. It seems quite simple, and foolproof, but many psychologists have begun to find holes in the argument for this. 

Research done by Moncrieff et al includes compelling data suggesting that there is no consistent evidence linking lowered serotonin concentration or activity to depression. They therefore suggest it is “time to acknowledge the serotonin theory of depression is not empirically substantiated.” This leads many to question the effectiveness of SSRIS. But how could that be? For the most part, patients who use SSRIS report their symptoms of depression and anxiety decreasing significantly, as well as their mood stabilizing. It is possible that this is partially because of a placebo effect, which is when a person’s belief in the treatments is what is causing their improvement, and not the treatment itself. It is also possible that researchers claims do not hold as much truth as they believe. Despite there clearly being evidence of a lack of a correlation, there is also decades worth of evidence that SSRIS do work. 

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Furthermore, it is important to note that we do not understand everything about SSRIS. The brain, and therefore, psychiatric medications, are incredibly complex. We tend to find that there isn’t just one answer to the psychology questions we seek, especially when considering that everyone is different, and there are lots of things we still don’t know about the brain. Psychiatrists and psychologists alike do not suggest stopping SSRIS if you are on one, especially not without consulting your physician. As research continues, we hope to find more of the answers we seek, although it’s hard to say what the near future holds for current theories about SSRIS and other psychiatric medications. 

Sources: 

https://www.mayoclinic.org/diseases-conditions/depression/in-depth/ssris/art-20044825

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9669646/#B17

https://www.psychologytoday.com/us/blog/denying-the-grave/202209/we-still-don-t-know-how-antidepressants-work

https://www.nhsinform.scot/tests-and-treatments/medicines-and-medical-aids/types-of-medicine/selective-serotonin-reuptake-inhibitors-ssris#:~:text=It’s%20 thought%20to%20have%20a,messages%20between%20 nearby%20never%20 cells.

https://www.cdc.gov/nchs/products/databriefs/db377.htm

New drug clinically slows down cognitive decline in Alzheimer’s patients by 35%

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Donanemab, “seen as a turning point in dementia fight,” as per a report from the BBC, is a drug that has slowed cognitive decline of the symptoms of dementia/Alzheimer’s by 35% (as per data presented July 17 at the Alzheimer’s Association International Conference in Amsterdam).

This antibody can temporarily put a hold to the effects of the disease on the patient. “The rationale behind Donanemab is that targeting deposited plaque itself is necessary to clear existing amyloid burden from the brain, rather than merely prevent deposition of new plaques or growth of existing plaques.” (Source: https://www.alzforum.org/therapeutics/donanemab)

Donanemab is primarily targeted towards patients in the early stages of the disease, and has shown significant results depicting an optimistic future in finding a cure/cures for the disease. 

Before continuing, it should be known that though the symptoms of Alzheimer’s disease and dementia diseases are similar, their causes are usually different. Generally, all diseases that contribute to memory loss are due to nerve cell damage and plaque build up, and Alzheimer’s disease is no different.

It is caused due to the abnormal or excess build up of protein in and around brain cells, and all diseases that come under dementia are due to nerve cell damage. Amyloid is one such protein that is most commonly present in Alzheimer’s disease patients. 

Dementia is somewhat of an umbrella term, and includes various diseases and conditions that contribute to memory loss and odd behavior, Alzheimer’s disease being one, Parkinson’s disease, Chronic Traumatic Encephalopathy (CTE) among others. 

Denenomab specifically targets the Amyloid protein, and is therefore subjected for Alzheimer’s disease, not other dementia diseases.

Previously, the FDA (food and drug administration) gave approval to another drug, Lecanemab, another drug whose main goal is to slow down cognitive decline as well. Both of these drugs aim to remove amyloid plaque from the brain, which is presumed to be the cause of the disease in the first place.

In a nutshell, the main purpose of Donanemab is to clear amyloid plaque present in the brain, which is usually present in Alzheimer disease patients. 

It should be noted that these drugs do have side effects, some concerning, such as internal brain bleeding and/or swelling, and even four deaths – three of whom were tested in the Donanemab group. Though the probability of such risks are rare, intensive research and development is still required until they can officially be licensed as drugs. 

It should also be understood that the drug doesn’t stop cognitive decline, it is just that it slows or delays the symptoms of cognitive decline, and that the known symptoms are bound to be visible in patients over an extended period of time.

As per JAMA, “Donanemab significantly slowed Alzheimer disease progression, based on the iADRS (Integrated Alzheimer’s Disease Rating Scale) score.” 

This new drug could possibly open doors to finding a temporary cure for the disease, and make it long lasting instead of permanent – similar to diabetes or asthma. 

References:

John R. Sims, MD. “Trial of Donanemab in Early Symptomatic Alzheimer Disease.” JAMA, JAMA Network, 17 July 2023, jamanetwork.com/journals/jama/fullarticle/2807533. 

MC, Irizarry, et al. “Donanemab.” ALZFORUM, www.alzforum.org/therapeutics/donanemab. 

FDA Grants Accelerated Approval for Alzheimer’s Disease Treatment, https://www.fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-alzheimers-disease-treatment