Do antipsychotic drugs work? | Andrew Scull and Lex Fridman

Andrew Scull, a medical historian, discusses the complex reality of antipsychotic medication efficacy and safety with Lex Fridman. He begins by establishing that antipsychotics work for some patients but not others, similar to how antidepressants fail for many people with depression. Scull then details the serious side effects that were initially downplayed or ignored by the psychiatric profession, including akathisia (constant restlessness and motion), Parkinsonian symptoms, and tardive dyskinesia—late-onset involuntary jerky movements primarily affecting facial muscles and tongue, which can create a stigmatizing appearance.

Scull explains that tardive dyskinesia was largely ignored for approximately 20 years until psychiatrist George Crane published a landmark paper in Science (around the 1960s) highlighting the profession's failure to address this iatrogenic harm. By the 1980s, the American Psychiatric Association and drug companies became concerned. Clozapine, developed in 1957 but initially rejected for the American market due to its tendency to destroy white blood cells (causing patient deaths), was revisited as a potential solution to the tardive dyskinesia problem. It was successfully reintroduced in the late 1980s, but required weekly blood checks as a safety measure. This led to the development of a new class of "second-generation antipsychotics" including Risperdal and Zyprexa.

Scull critically addresses the drug approval and research process, explaining that pharmaceutical companies funded studies, controlled data, and only released favorable results. For FDA approval, companies only needed two successful trials out of potentially 15 conducted—a practice he finds problematic. The pivotal 2005 CATIE study, funded by the National Institute of Mental Health (not industry), compared a cheap first-generation antipsychotic with four newer, expensive second-generation drugs. The findings were striking: the new drugs were not more efficacious than the old drug, and 67-82% of patients dropped out due to drug inefficacy or unbearable side effects.

Regarding side effects of second-generation drugs, Scull describes a new profile: while tardive dyskinesia decreased somewhat, patients experienced significant weight gain (10-50+ pounds), leading to metabolic syndrome, diabetes, and heart disease. He emphasizes that all medications involve cost-benefit analysis—the relief from psychiatric symptoms must be weighed against new dangers that may or may not materialize. Critically, there are currently no biological markers to predict which patients will respond well, which will experience severe side effects, or which will suffer cognitive/personality changes. Scull notes that some patients drop out specifically because they experience a loss of mental richness and personality, preferring to tolerate hallucinations rather than the emotional flattening caused by medication.