KELLIE NEWSOME: The Epstein story gets stranger and reaches its tentacles into psychiatric journals and the anti-psychiatry movement in today's episode, When Jeffrey Meets Ghislaine. Welcome to The Carlat Psychiatry Podcast, keeping psychiatry honest since 2003.

CHRIS AIKEN: I'm Chris Aiken, the editor-in-chief of The Carlat Psychiatry Report.

KELLIE NEWSOME: And I’m Kellie Newsome, a psychiatric NP and a dedicated reader of every issue. In our last episode, we traced Epstein’s early years up to 1994. We saw him cross boundaries and break some rules, but nothing like the typical biography of a burgeoning antisocial. Today, we’ll tell the story of how Jeffrey Epstein met Ghislaine Maxwell. Come along, and you’ll learn some psychiatric facts along the way, like whether money leads to happiness, what kind of stress causes depression, and why the FDA changed their requirements for new drug approvals last month. But first, a preview of the CME quiz, which you’ll find in the show notes

1. According to a 2003 twin study, which pair of stresses have the strongest link to depression?

A. Threat and defeat

B. Threat and loss

C. Defeat and humiliation

D. Loss and humiliation

CHRIS AIKEN: It's not until 1994 that we have the first clear report of abuse of a minor by Epstein, and this wasn't made public until last December. The setting was the Interlochen Arts Camp in Michigan, the same camp where a 14-year-old Epstein played bassoon on a scholarship years before. Now 42 and wealthy, Epstein returns to the camp as a benefactor, donating money to build a cabin for scholarship students officially christened as the Epstein Lodge. He remained a patron of the camp for another decade. Interlochen cut ties with Epstein in 2008 when they learned of his abuses. The cabin still stands but is now known as Green Lake Lodge.

KELLIE NEWSOME: Epstein did not travel to Interlochen alone on that summer day in 1994. He took with him a new girlfriend, Ghislaine Maxwell, daughter of the billionaire publisher Robert Maxwell. Robert is best known as the publisher of tabloid newspapers like the Daily Mirror and the New York Daily News, but he was also one of the first to spot the profit potential of scientific journals. Through Pergamon Press, he published over 700 scientific journals, including the Journal of Psychiatric Research. While Pergamon featured psychiatric journals and textbooks, another Maxwell company, Macmillan Press, turned out popular anti-psychiatry books by Michel Foucault, Peter Breggin, and others. This wasn’t the first time Maxwell profited from opposing factions. As a soldier in World War II, he ran a black market across enemy lines. During the Cold War, he spied for both the Soviet KGB and Britain’s MI6, playing them against each other. But Robert’s appetite for expansion was also his downfall. Compounding many media acquisitions left him dangerously in debt, with assets of one billion and debts of two billion. To cover those debts, he embezzled half a billion dollars from his employees’ retirement accounts. It wasn’t his first antisocial act. He bullied employees, fabricated his life story, manipulated stock prices, and physically abused his children, including his favorite, Ghislaine. After his helicopter landed on top of the Daily Mirror headquarters, Maxwell would often stop to urinate off the eleven-story building onto unsuspecting passersby. Ironically, he died in the same fashion – urinating off the deck of his yacht, the Lady Ghislaine. The conspiracy is that he was killed by Israeli Mossad intelligence, and though it’s well documented that Robert Maxwell spied for Mossad and recent emails from Jeffrey Epstein endorse this conspiracy, the claim is unconfirmed, as is the claim that Epstein spied for Mossad.

CHRIS AIKEN: Tying those conspiracies together is another rumor that Robert Maxwell introduced Ghislaine to Epstein shortly before his death in 1991, and this rumor finds new support in recently released FBI interviews. But however they met, it was a stroke of good fortune for Ghislaine, who was left almost penniless by her father's debts. Well, almost penniless. She did inherit a trust fund that paid her 80,000 pounds a year, which in today's money is about $280,000 US dollars a year. That's enough to ensure happiness, according to Nobel laureate Daniel Kahneman, whose 2010 study tells us that happiness rises with higher income but only to a certain point, peaking at around $115,000 a year, for a single person, in today's dollars. But Kahneman's research doesn't look at those who fall from the billionaire class to the mere upper class. To fill those gaps, we need to look at an earlier study that interviewed people who lost their retirement savings in a 1985 bank fraud. After the loss, they had three times the rate of generalized anxiety disorder and 15 times the rate of depression compared to controls. Even without fraud involved, the effects of loss of wealth are significant. After the 2008 stock market crash, the suicide rate went up 40% in Korea.

KELLIE NEWSOME: In Ghislaine's case, the fraud was committed by her father, but I imagine that could make it worse. One of Bernie Madoff's sons died by suicide after his father's fraud was exposed. Ghislaine lost a father, her family's reputation, and what she thought was a billion-dollar empire in a single day.

CHRIS AIKEN: It's a double dose of the two stresses that have the strongest links to depression: loss and humiliation. Kenneth Kendler is a psychiatric researcher known for uncovering the genetic basis of mental illness through twin studies. But in 2003, Kendler turned that technique on its head to figure out not how genes cause mental illness, but how stress leads to depression.

KELLIE NEWSOME: Why do you need twin studies to do that? We know that stress causes depression.

CHRIS AIKEN: In a way, but there's always been this nagging possibility that genetic factors are behind it all. Here's how that looks. Suppose a person has a genetic temperament that makes them more avoidant and prone to make bad decisions in life. These people are going to get into more stress, so they'll just have more stress in their life because of their genes, and that stress is going to trigger more depression, but the cause here is still in the genes. So Kendler and his team tried to use twin studies to unravel these associations, and they found they could attribute most stresses to this underlying temperamental link. But at least one stressor stood out as causing depression regardless of underlying temperament, and that was stressors involving loss paired with humiliation. So when you lose your family to divorce, but it's humiliating as well because your spouse cheated on you, there's loss and humiliation. Or when you lose your father and are humiliated by the fraud he committed before his death.

KELLIE NEWSOME: Whether or not Ghislaine Maxwell was depressed after her father's death, we don't know. But we do know her fall was buffered by Epstein. He filled the wealth gap, buying her an expensive townhouse on the Upper East Side. Ghislaine, in turn, provided Epstein with social connections, like the former Prince Andrew. They complemented each other, and they also had a shared interest in crossing sexual boundaries. Back to Interlochen camp, the summer of 1994. Ghislaine and Jeffrey approached a 13-year-old vocal student, offering mentorship and financial support for her continued education. Jeffrey Epstein is 42. According to newly released documents, they allegedly brought her to his Florida mansion, where Ghislaine normalized nudity and massages that culminated in the sexual assault of Epstein’s first recorded victim. Other victims followed. In 1996, a 26-year-oldartist reported abuse of herself and her 16-year-old sister to the FBI, but the report went unheeded. By the late 1990s, the two had developed an efficient, secretive operation. Ghislaine recruited young girls with the promise of modeling opportunities, massage training, or educational support. She directed the girls to massage Jeffery, who turned the massages into sexual assaults, sometimes with Ghislaine’s help. They were paid $200 and offered another $200 if they brought other young girls to do the same. The victims, then, were turned into co-conspirators, and Epstein manipulated their feelings of guilt to maintain their silence as the enterprise grew.

CHRIS AIKEN: That silence broke in March of 2005 when the mother of a 14-year-old girl reported the abuse to the Palm Beach Police. The investigation exposed a ring of around 50 exploited minors. In 2008, Epstein negotiated a plea deal where he would serve only 18 months if he pleaded guilty to a lighter charge of solicitation of prostitution from a minor. He served only 13 of those 18 months and was allowed to go home on a pass for 12 hours a day during his sentence in a low-security prison. In securing this deal, the federal prosecutors led by Alex Acosta turned over the case to the local courts, allowing Epstein to escape the federal charge of child sex trafficking. Those charges would have landed him behind bars for at least 10 years, and possibly for life. It was a new statute enacted in 2000, and Acosta was not comfortable testing it, especially against Epstein's well-funded legal team and political connections. So Acosta turned it over to the state, where Florida's law was more archaic, allowing children to be considered prostitutes and partly culpable for the crime. Under federal law, a child cannot be a prostitute because minors cannot consent to sex, and the blame falls entirely on the adult.

KELLIE NEWSOME: And that was just the beginning of the problems with this case. Acosta kept the agreement hidden from the victims, a violation of the Crime Victims’ Rights Act, and promised not to charge any co-conspirators who abused them. The unusual lenience has fueled speculation that Epstein was a government asset, providing international secrets or insider information about the 2008 financial collapse in exchange for a light sentence, but nothing solid has come to light in the 20 years since, or in the 6 million Epstein files that have recently been released.

STEVE BANNON: And told them that the money was coming from a, what are you, a class three sexual predator?

JEFFREY EPSTEIN: Tier one.

STEVE BANNON: Tier one. Tier one's the highest and worst.

JEFFREY EPSTEIN: No, it's—I'm—

STEVE BANNON: The lowest?

JEFFREY EPSTEIN: I'm the lowest.

STEVE BANNON: You're the lowest. Okay. Tier one, you're the lowest, but a criminal.

JEFFREY EPSTEIN: Yes.

KELLIE NEWSOME: Whatever the reason, Epstein walked away unharmed. He talked the Manhattan District Attorney into lowering his sex offender status, and re-entered high society as if nothing had happened. And it all might have stayed that way, except that Ghislaine Maxwell pushed their luck too far. In 2015, Maxwell accused one of their victims, Virginia Giuffre, of lying about the abuse. Giuffre sued Ghislaine for defamation, and that lawsuit allowed the Miami Herald to unseal the legal documents and expose the full story. The article arrived in 2018, at the height of the MeToo movement, a year into the first Trump administration, and an inflamed public learned that the same Alex Acosta who let Epstein walk was now the Secretary of Labor, a job that required him to protect victims of sexual harassment and labor trafficking. The scandal forced Acosta to resign, and inspired a team of federal prosecutors in New York to prosecute Epstein. His special deal with Acosta only applied to Florida, not to crimes committed in other states, and with fresh evidence of New York abuses, they arrested Epstein on July 6, 2019, for sex trafficking minors. A month later, he was found dead in his cell.

CHRIS AIKEN: Today's research update is not a new finding but a new paper that will change how science informs practice. Published by FDA Commissioner Martin Makary and FDA Director of Biologics Vinay Prasad, the paper in the New England Journal of Medicine is titled “One Pivotal Trial, the New Default Option for FDA Approval - Ending the Two-Trial Dogma“.

KELLIE NEWSOME: Here’s the background: since the 1960’s, the FDA has required two well designed trials to approve medications. That started to change under the FDA Modernization Act of 1997, which opened the door to one-trial approval. But so far, the agency has only allowed single-trial approvals through accelerated pathways for drugs that bring a new approach or address an unmet need. 

CHRIS AIKEN: Those accelerated pathways have exploded as companies find clever ways to classify their treatments as breakthroughs. Sixty-five percent of all drug approvals were approved this way in the past 10 years, and the rate is even higher in psychiatry. It started with the VMAT-2 inhibitors for tardive dyskinesia, which was a genuine unmet need, and expanded to Spravato, Auvelity, Cobenfy, Zulresso, three new medications for dementia, and this year, two devices for depression, Flow and ProlivRx.

KELLIE NEWSOME: Besides one well-designed clinical trial, the FDA will require another source of support, like animal models or a mechanism of action, but they have not done a good job of upholding this requirement in the accelerated pathway.

CHRIS AIKEN: The bottom line: on the pro side, the policy will bring more treatment options to the market. The disadvantage: more false positives and more uncharted risks. Clinicians are going to need to do a better job of policing themselves, which, if we do it right, could have a positive side. For too long, we've deferred to the FDA as the gold standard, and that devotion has tied us to the only organization that can afford the FDA's application fees: the pharmaceutical industry. Say if I give a lecture on major depression and I mention light box or even lithium, it's treated as suspect. I have to sign special disclosures about the off-label use. But if I only talk about SSRIs and antipsychotics, I'm clean as a whistle.

KELLIE NEWSOME: Here’s another problem. Most FDA approvals in psychiatry are based on short-term trials in long-term disorders. In Dr. Aiken’s new book Difficult to Treat Depression, you’ll learn that many of these approved medications work no better than placebo after a few months, while some off-label options keep preventing new episodes for several years.

CHRIS AIKEN: Our audio excerpt is from a 2019 interview taken shortly before Epstein’s death, of Steve Bannon, and released by the Department of Justice.