Why Serotonin Theory Falls Short

There’s no blood test for depression, no MRI or CT scan that can detect it. Because depression, like a lot of things involved with mental health, is invisible. 

Still, depression is the most common mental health issue in the US and worldwide. Nearly 30% of Americans will be diagnosed with depression in their lifetimes.

Many people wind up taking an antidepressant. You’ve probably heard of these drugs by their brand names: Prozac Lexapro, Paxil and - the drug in this episode - Zoloft.

These drugs do help, but finding the right drug that works for the right person can take a lot of time, and a lot of trial and error. This can be a messy and frustrating process.

In this episode of Drug Story, we jump into that mess. We explore the mystery of how these drugs actually work - and why depression seems so much more common today than in the past.

Sources for this episode:

[1] History of depression through the ages (2020) Archives of Depression and Anxiety: From Hippocrates’ humoral theory to Freud, key historical figures shaped the understanding and treatment of depression.

[2] History of Depression (2015) The Oxford Handbook of Mood Disorders: Symptom-focused diagnosis and treatment have contributed to the medicalization of normal human sadness.

[3] Minnesota Multiphasic Personality Inventory (2023) StatPearls: Developed in the 1930s and published in 1942, the Minnesota Multiphasic Personality Inventory (MMPI) is the most common psychometric test for assessing personality traits and psychopathology including depression.

[4] The development of Minnesota Multiphasic Personality Inventory (1994) Journal of the History of the Behavioral Sciences: Two scientists at the University of Minnesota, Starke Hathaway and J. C. McKinley, developed the MMPI in the 1930s, a widely adopted survey measuring mental illness.

[5] Depression as a disease of modernity: Explanations for increasing prevalence (2012) Journal of Affective Disorders: Modern lifestyle factors like poor diet, inactivity, and social isolation may contribute to rising depression rates.

[6] The creation of the concept of an antidepressant: An historical analysis (2008) Social Science & Medicine: The term antidepressant gained traction in the 1950s-1960s, framing drugs as disease-specific treatments for depression.

[7] A RATING SCALE FOR DEPRESSION (1960) Journal of Neurology, Neurosurgery & Psychiatry: Max Hamilton published the Hamilton Rating Scale for Depression (HAM-D) questionnaire to measure severity of depression symptoms.

[8] The PHQ-9 (2001) Journal of General Internal Medicine: The Patient Health Questionnaire (PHQ-9) is a nine-item depression symptom questionnaire used to screen adults for depression. Kurt Kroenke developed the PHQ in the mid-1990s with funding from Pfizer. 

[9] The Origin Story of the Zoloft Sad Blob, a Clinically Depressed Icon (2021) Mel Magazine: Early 2000s ads used a blob character to represent depression, which drew both praise and criticism.

[10] Serotonin and Depression: A Disconnect between the Advertisements and the Scientific Literature (2005) PLoS Medicine: SSRIs are marketed as correcting a serotonin deficiency, despite a lack of conclusive scientific evidence.

[11] Antidepressants Don’t Work the Way Many People Think (2022) The New York Times: Experts note that the chemical imbalance theory of depression is outdated.

[12] Development of the commercial process for Zoloft®/sertraline (2005) Chirality: Continuous chromatography enabled efficient large-scale production of sertraline.

[13] The Architect of Zoloft (2015) Reed Magazine: Kenneth Koe modified tametraline compounds to block serotonin reuptake, leading to sertraline hydrochloride’s release as Zoloft in 1992.

[14] ACS Award for Team Innovation (2006) Chemical & Engineering News: Zoloft’s discovery was led by Pfizer scientists Reinhard Sarges, B. Kenneth Koe, Willard M. Welch, Albert Weissman, and Charles A. Harbert.

[15] Sertraline versus other antidepressive agents for depression (2010) Cochrane Database of Systematic Reviews: Sertraline is a selective serotonin reuptake inhibitor (SSRI) used as a first-line treatment for major depression, with evidence demonstrating superior efficacy over other antidepressants.

[16] Do Antidepressants Work? (2018) The New York Times: In multiple meta-analyses of antidepressant trials, researchers confirm that while antidepressants are more effective than placebos for treating acute major depression, the actual clinical benefits are mostly modest. Study design, participant selection, and publication bias may result in more favorable evidence supporting the use of antidepressants.

[17] What Obesity Drugs and Antidepressants Have in Common (2023) The New York Times: Aaron Carroll writes that because science cannot fully explain the biological mechanisms of mental health and obesity drugs, these treatments are stigmatized and incorrectly viewed as a lack of willpower rather than medically necessary.

[18] The STAR*D study: treating depression in the real world (2008) Cleveland Clinic Journal of Medicine: The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Trial established that 70% of patients with clinical depression could achieve remission using antidepressants after following a four-step sequence of switching various treatments until they found relief. 

[19] The STAR*D Trial: It Is Time to Reexamine the Clinical Beliefs That Guide the Treatment of Major Depression (2015) The Canadian Journal of Psychiatry: A reexamination of The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Trial argues the original findings from the study were overestimated due to poor study design and bias.

[20] Restoring STAR*D: A Reanalysis of Drug-Switch Therapy After Failed SSRI Treatment Using Patient-Level Data with Fidelity to the Original STAR*D Research Protocol (2025) medRxiv: A reanalysis of the STAR*D data found that switching antidepressants provides minimal benefit and has a higher risk-to-benefit ratio than stated in the original trial.

[21] Effectiveness of antidepressants: an evidence myth constructed from a thousand randomized trials? (2008) Philosophy, Ethics, and Humanities in Medicine: An analysis of antidepressant data submitted to the FDA reveals selective reporting and publication bias that mask negative results, leading to an inflated perception of drug benefits.

[22] Clinical Practice Guideline for the Treatment of Depression Across Three Age Cohorts (2019) American Psychological Association: Evidence-based recommendations for treating depressive disorders in children, adults, and older adults.

[23] Predictive biomarkers could ease the exhaustive trial-and-error of antidepressants (2023) STAT: Research aims to identify biomarkers to reduce the trial-and-error of antidepressant prescribing.

[24] AI Tool Matches Patients to Effective Antidepressants Faster (2024) Neuroscience News.com: Platforms like MeAgainMeds.com aim to reduce trial-and-error in finding effective antidepressants.

[25] More treatment but no less depression: The treatment-prevalence paradox (2022) Clinical Psychology Review: Despite advances in treatment, depression prevalence has not decreased since the 1980s.

[26] How Sertraline (Zoloft) Completely Changed My Life (2024) @itsblakematthew: Blake Matthews details his experience with Zoloft.