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.

Once you turn 40, it seems like half the people you know are taking a statin drug. You know, because their cholesterol is high, and to prevent heart disease down the line. It makes sense: better safe than sorry.

This is a huge triumph for preventive medicine. Statin drugs have saved (or improved) the lives of millions of people because they acted early. This is how medicine (and public health) is supposed to work.

But the devil is in the details. Like all drugs, statins have side effects. And when they are prescribed for many millions of people, the math means that millions of people will not, in fact, get any benefit from the drug. It turns out that atorvastatin (and other statin drugs) may be the most over-prescribed drugs in the history of medicine. And therein lies a Drug Story.

Sources for this episode:

[1] Akira Endo- Gairdner Gala Acceptance Speech (2017) Canada Gairdner Awards: Akira Endo, the Japanese biochemist who discovered the first statin, reflects on American dietary and lifestyle habits that inspired him to develop a solution to prevent heart disease.

[2] Influence of nicotinic acid on serum cholesterol in man (1955) Archives of Biochemistry and Biophysics: Since 1955, the B-vitamin niacin (nicotinic acid) has been used in the treatment of high cholesterol.

[3] Atherosclerotic Cardiovascular Disease Risk Estimates Using the Predicting Risk of Cardiovascular Disease Events Equations (2024) JAMA Internal Medicine: The Predicting Risk of Cardiovascular Disease Events (PREVENT) cardiovascular risk equation excludes race, adds kidney function and statin use, and suggests fewer adults may be eligible for statins compared to pooled cohort equations.

[4] It Took A Brilliant Marketing Campaign To Create The Best-Selling Drug Of All Time (2011) Business Insider: Lipitor became the best-selling drug of all time through aggressive marketing to doctors and coinciding with the FDA?s allowance of direct-to-consumer drug advertising in 1997.

[5] Learning From Our Parents? Heart Health Mistakes (2017) The New York Times: Indigenous South Americans, the Tsimane, have low rates of coronary artery disease and healthier lifestyles compared to Americans, offering a model for prevention.

[6] CHOLESTEROL: DRUG HAILED AS TREATMENT BREAKTHROUGH (1987) The New York Times: The New York Times introduces lovastatin, a novel drug predicted to revolutionize the treatment of high cholesterol.

[7] Millions fewer people may need statins, a new study suggests. But guidelines have yet to agree (2024) STAT: The number of adults recommended for statins could drop from 45.4 million to 28.3 million based on new risk calculations.

[8] A historical perspective on the discovery of statins (2010) Proceedings of the Japan Academy: Akira Endo?s discovery of compactin from fungal cultures led to lovastatin, the first commercial statin.

[9] The Role of Lipids and Lipoproteins in Atherosclerosis (1950) Science: John Gofman discovered LDL cholesterol and its correlation with atherosclerosis through ultracentrifugation of plasma lipoproteins.

[10] Statins for Primary Cardiovascular Disease Prevention: Time to Curb Our Enthusiasm (2022) JAMA Internal Medicine: Cardiologists question the benefit of statins for individuals with low cardiovascular disease risk, citing limited evidence.

[11] History of the Framingham Heart Study (1957) Framingham Heart Study: The Framingham Heart Study identified key cardiovascular risk factors, including high cholesterol, blood pressure, smoking, obesity, diabetes, and inactivity.

[12] ?For Me There Is No Substitute?: Authenticity, Uniqueness, and the Lessons of Lipitor (2010) American Medical Association Journal of Ethics: Lipitor backlash followed when it was revealed that Dr. Robert Jarvik, spokesperson in Lipitor ads, was not licensed to practice medicine and misrepresented his credentials.

[13] Lipitor a story of rags to riches (2011) Arkansas Democrat-Gazette: Lipitor achieved success by lowering LDL cholesterol more effectively than competitors, aided by expanded statin eligibility guidelines.

[14] History in medicine: the story of cholesterol, lipids and cardiology (2021) e-Journal of Cardiology Practice: Cardiology research has an extensive history: from its identification in gallstones in 1769 to Nobel Prize-winning discoveries on lipids and atherosclerosis.

[15] Discovery of Lipitor (2009) Triumph of the Heart: The Story of Statins: Despite being the fifth statin introduced, Lipitor dominated the market due to superior LDL-lowering efficacy.

[16] Counting Cholesterol (1987) The MacNeil/Lehrer NewsHour: Merck?s Mevacor became the first FDA-approved statin and cholesterol-lowering drug.

[17] Cardiovascular Disease Resulting From a Diet and Lifestyle at Odds With Our Paleolithic Genome: How to Become a 21st-Century Hunter-Gatherer (2004) Mayo Clinic Proceedings: High cholesterol may stem from a mismatch between modern diets and Paleolithic human biology.

[18] What Will the New Cardiovascular Risk Calculator Mean for Patients? (2024) Harvard Medical School: The Predicting Risk of Cardiovascular Disease Events (PREVENT) model could significantly reduce the number of statin-eligible adults.

[19] Pfizer Gets Its Deal to Buy Warner-Lambert for $90.2 Billion (2000) The New York Times: Pfizer purchased Lipitor?s manufacturer for $90.2 billion.

[20] Pharmaceutical Mycelia: A story of statins LGC Standards: Early statins derived from Penicillium and Aspergillus inhibit HMG-CoA reductase to lower cholesterol.

[21] A New Women?s Issue: Statins (2014) The New York Times Well Blog: Cardiologists raise concerns over limited evidence for statin benefits in women due to underrepresentation in trials.

[22] Statins for Primary Prevention: The Debate Is Intense, but the Data Are Weak (2016) JAMA: Researchers highlight inflated benefits of statins and incomplete adverse event data.

[23] Medical Marketing in the United States, 1997-2016 (2019) JAMA: U.S. medical marketing expenditures rose from $17.7B in 1997 to $29.9B in 2016, with limited regulation of misleading ads.

[24] Thematic review series: The Pathogenesis of Atherosclerosis. An interpretive history of the cholesterol controversy: part I (2004) Journal of Lipid Research: Nikolai Anitschkow induced vascular lesions in rabbits by feeding them cholesterol, resembling human atherosclerosis.

[25] Thematic review series: The Pathogenesis of Atherosclerosis. An interpretive history of the cholesterol controversy: part II: the early evidence linking hypercholesterolemia to coronary disease in humans (2005) Journal of Lipid Research: Research supported lowering cholesterol through dietary changes; confirmed in the Framingham Heart Study.

[26] Primary nonadherence to statin medications: Survey of patient perspectives (2021) Preventive Medicine Reports: In this study, over half of the patients prescribed statins but not taking them never informed their prescribers, often preferring lifestyle changes or natural remedies.

Epipen is an exquisitely engineered, expertly marketed, totally modern drug. And it?s an amazing success story, especially if you count success through dollars - Epipen sales rose from $200 million in 2007 to $1 billion a year in 2015 to more than $2 billion in 2023. Epipen is what they call in the pharma business, a blockbuster.

The story of Epipen is also a story of unintended consequences and unexpected discoveries, one that goes from the Azores, some islands in the middle of the Atlantic Ocean, to Sweden, the home of the Nobel Prize, to Vietnam, during the Vietnam War.

This story also lands very close to home. Today, Epipens are in schools, they?re in malls, they?re on airplanes, they may even be in your backpack or purse or glove compartment - just in case. So in this episode, we?ll learn all about that.

And there?s also the biggest unintended consequence of all. It turns out that for many of the millions of people like Alex who live with food allergies - and the risk of anaphylaxis - their condition may in fact be the result of one of the biggest blunders of the past century of medicine and public health.

Sources for this episode

[1] A Mighty Pen (2013) Science History Institute Museum and Library: In the 1970s, inventor Sheldon Kaplan developed an epinephrine autoinjector in response to the need for rapid, self-administered injections to treat anaphylactic shock.

[2] Auvi-Q Versus EpiPen: Preferences of Adults, Caregivers, and Children (2013) The Journal of Allergy and Clinical Immunology: This study evaluates preference for the Auvi-Q epinephrine autoinjector over the EpiPen among adults, caregivers, and children.

[3] Epinephrine Administered in Anaphylaxis: The Evolution of 0.3 mg Dosage (2023) Therapeutic Advances in Allergy and Rhinology: Anaphylaxis was first formally discovered by French scientists Charles Richet and Paul Portier in experiments with dogs. They found that dogs became more sensitive, rather than less sensitive, to a toxin after an initial small dose.

[4] Northeastern alumnus the genius behind life-saving EpiPen (2016) Northeastern Global News: Sheldon Kaplan reengineered a Cold War-era device, the ComboPen, that delivered a nerve agent antidote, into a device that delivered epinephrine. The new device, EpiPen, was patented under Kaplan?s name in 1977.

[5] Body and Mind; Backward Protection (1989) New York Magazine: Anaphylaxis is a biological mechanism where the immune system provides misguided ?backwards protection? by overreacting to allergens such as nuts, penicillin, or insect stings.

[6] The Use of Adrenal Substance In the Treatment of Asthma (1900) Journal of the American Medical Association: Early research by Dr. Solomon Solis-Cohen showed that using extracts from animal adrenal glands could significantly relieve asthma symptoms by strengthening blood vessels and reducing swelling in the airways.

[7] The Allergy Epidemics: 1870?2010 (2015) The Journal of Allergy and Clinical Immunology: The rise in allergies over the past 150 years can be attributed to advances in hygiene and lifestyle changes, such as increased sedentary indoor lifestyles.

[8] History of food allergy and where we are today (2024) World Allergy Organization Journal: Once poorly understood, food allergies are now managed through strategies beyond avoidance, including immunotherapy, biologic treatments, and early allergen introduction for prevention.

[9] How Marketing Turned the EpiPen Into a 20 Billion-Dollar Business (2015) Bloomberg Businessweek: Mylan Pharmaceuticals, the manufacturer of EpiPen, ran marketing campaigns emphasizing the dangers of food allergies and lobbied lawmakers to place EpiPens in schools and public venues. As a result, the EpiPen became a $1 billion-per-year product, and its price increased by 400% after Mylan acquired it in 2007.

[10] Epinephrine: a short history (2015) The Lancet Respiratory Medicine: In 1894, the English physician George Oliver and the English physiologist Edward Schafer discovered the physiological effects of adrenal medulla extract. In 1899, American biochemist John Jacob Abel successfully purified the extract?s active ingredient and named it epinephrine. It was then synthesized in ampules by Parke-Davis & Company in 1909.

[11] The ancestry of allergy: Being an account of the original experimental induction of hypersensitivity recognizing the contribution of Paul Portier (1985) The Journal of Allergy and Clinical Immunology: In 1902, Paul Portier and Charles Richet discovered anaphylaxis after observing that a second, weak injection of sea anemone toxin caused fatal hypersensitivity in dogs rather than the expected immunity.

[12] Feed Your Kids Peanuts, Early and Often, New Guidelines Urge (2017) The New York Times: The National Institute of Allergy and Infectious Diseases shifted its approach to child nutrition in 2017 by recommending that parents introduce peanut-based foods to infants as early as four to six months of age.

[13] Portier, Richet, and the discovery of anaphylaxis: A centennial (2002) The Journal of Allergy and Clinical Immunology: Paul Portier and Charles Richet discovered anaphylaxis while investigating the toxins of marine life aboard the yacht of Prince Albert of Monaco in 1901.

[14] The Prevalence of Chronic Respiratory Disease in the Industrial Era The United States, 1895?1910 (2003) National Bureau of Economic Research: Chronic respiratory disease prevalence rose in the United States between 1895 and 1910 due to rapid urbanization, industrial pollution, and the emergence of cigarettes.

[15] Shock Reaction Following Ingestion of Mango (1965) Journal of the American Medical Association: A case study on an anaphylactic-like response to mango helped establish early clinical understanding of food-induced anaphylaxis.

[16] Slow Epinephrine In the Treatment of Chronic Asthma (1939) The Journal of Allergy: This 1938 study shows that mixing epinephrine with peanut oil allows the body to absorb the medicine more slowly than the standard water-based version. By delaying absorption, patients can reduce the frequency of injections.

Diabetes and anxiety and insomnia and depression and food allergies. For every modern malady, there are drugs promising to fix it. SO MANY DRUGS.

But they never really fix the problem, do they? Yes, drugs can help people manage their disease. They treat the symptoms. But they rarely remedy what caused the disease in the first place. And therein lies a story. Launching Jan. 6, 2026.