Talking Back to Prozac: What Doctors Won’t Tell You About Today’s Most Controversial Drug (2014)

By Peter & Ginger Breggin – 36 Q&As – Unbekoming Book Summary

I’ve touched on Prozac before.

The Poisoning - Lies are Unbekoming

Freya India

• Popular SSRIs include Fluoxetine (Prozac), Escitalopram (Lexapro), and Sertraline (Zoloft). Something well established about these drugs is that they have sexual side-effects. In fact, between 40 and 65% of people who take an SSRI are thought to experience some form of sexual dysfunction. What few people know, though, is these side effects can persist even after coming off of the drugs—a condition called Post-SSRI Sexual Dysfunction (PSSD).

• There is no treatment. Despite PSSD being in the medical records since the ‘90s, patients are rarely warned of the risk. A risk thought to be 1 in 216.

• In fact, according to this Stonewall report, more Gen Z Brits identify as asexual (5%) than gay (2%) or lesbian (3%).

Mass Shootings - Lies are Unbekoming

• Jeff Weise, age 16, had been prescribed 60 mg/day of Prozac (three times the average starting dose for adults!) when he shot his grandfather, his grandfather’s girlfriend and many fellow students at Red Lake, Minnesota. He then shot himself. 10 dead, 12 wounded.

• Chris Fetters, age 13, killed his favorite aunt while taking Prozac.

• Kip Kinkel, age 15, (on Prozac and Ritalin) shot his parents while they slept then went to school and opened fire killing 2 classmates and injuring 22 shortly after beginning Prozac treatment.

• Luke Woodham, age 16 (Prozac) killed his mother and then killed two students, wounding six others.

• Jeff Franklin (Prozac and Ritalin), Huntsville, AL, killed his parents as they came home from work using a sledge hammer, hatchet, butcher knife and mechanic’s file, then attacked his younger brothers and sister.

• Neal Furrow (Prozac) in LA Jewish school shooting reported to have been court-ordered to be on Prozac along with several other medications.

I came across this book by the Breggins that I think is worth amplifying.

"Talking Back to Prozac" presents a critical examination of how Prozac and similar antidepressants gained FDA approval through questionable scientific practices and limited trials. The book reveals that only 286 patients completed the four to six-week trials used for FDA approval, with many studies showing no beneficial effects. Through careful analysis, it exposes how pharmaceutical companies manipulated data, excluded negative results, and conducted trials on a highly selective patient population while excluding high-risk groups like suicidal patients, children, and the elderly.

The book's central argument is that depression is not a simple chemical imbalance requiring drug intervention, but rather a complex human experience that demands understanding, empathy, and meaningful personal growth. It challenges the growing medicalization of normal human emotions and argues that turning to drugs often means turning away from life itself, preventing individuals from addressing the real underlying causes of their suffering and achieving genuine healing. The authors contend that people's capacity for deep suffering corresponds directly to their potential for living a rich, fulfilling life, and that drug intervention often interrupts this natural process of growth and recovery.

The book is obviously about Prozac but more importantly about the corruption of the “gatekeepers” that allows for the poisoning of citizens for profit and control.

With thanks to Peter & Ginger Breggin.

Talking Back to Prozac: What Doctors Won’t Tell You About Today’s Most Controversial Drug: Breggin, Peter R., Breggin, Ginger Ross

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Analogy

Imagine you're buying a car from a dealership. The dealer shows you impressive test drive results, but these tests were conducted only on flat roads, in perfect weather, for just 15 minutes each, and only with experienced drivers. They excluded testing on highways, in rain, with new drivers, or on steep hills. Yet the car is later sold to everyone - experienced and new drivers alike, for use in all conditions and terrains.

The dealer also combined the best results from multiple test drives while discarding the problematic ones, and some of the successful test drives included a professional mechanic in the passenger seat making real-time adjustments. When other mechanics raised concerns about the car's performance, the dealer emphasized the positive test drives and dismissed the negative reports.

This mirrors Prozac's FDA approval process - where short-term trials (4-6 weeks) on a limited population were used to justify widespread prescription, negative studies were discarded while positive ones were emphasized, and many patients in "successful" trials were actually taking additional medications. Just as a car should be thoroughly tested in all conditions it might face, a drug's safety and efficacy should be comprehensively evaluated for all its intended users and uses.

12-point summary

1. FDA Approval Process Flaws

The FDA approval of Prozac was based on questionable statistical manipulations and data pooling. Out of fourteen controlled study protocols submitted, only three showed beneficial effects while the majority demonstrated no positive effect. When individual studies failed, Eli Lilly was allowed to pool data from separate negative studies and exclude certain negative results to achieve statistical significance.

2. Limited Trial Size and Duration

Only 286 patients completed the four to six-week trials used for FDA approval, a remarkably small sample for such a widely prescribed medication. The trials were extremely short-term, with 86% of all patients treated for three months or less, making it impossible to assess long-term safety and efficacy.

3. Selective Patient Population

The trials deliberately excluded several major patient populations, including suicidal patients, hospitalized psychiatric patients, children, and elderly adults. This selective inclusion criteria meant that the drug's effects were only tested on a limited subset of the population, though it would later be prescribed to these excluded groups.

4. High Dropout Rates

Trial dropout rates sometimes reached 50%, with at least one-third of patients typically failing to finish. In Protocol 27, from an initial group of more than 700 patients, fewer than 150 Prozac patients remained, significantly impacting the statistical validity of the results.

5. Multiple Medication Use

Approximately one-third of patients in the trials received additional psychiatric medications, including minor tranquilizers and sedatives, alongside Prozac. This concurrent use made it impossible to determine whether positive results could be attributed to Prozac alone, effectively meaning the FDA approved Prozac in combination with sedatives.

6. Statistical Manipulation

When initial results were negative, Eli Lilly repeatedly reworked the numbers by removing certain data sets and reincluding others. In Protocol 27, they excluded 25% of the total protocol patients and reincluded patients who had taken additional psychiatric drugs to finally achieve positive results on four measurements of improvement.

7. Limited Adverse Effect Detection

The pooled data for adverse reactions from all premarketing studies involved approximately 4,000 patients, an insufficient number to screen for relatively uncommon dangerous drug reactions. A fatal reaction occurring once in every 4,000 patients might not appear in trials but could cause significant harm when prescribed to millions.

8. Industry Influence

The book reveals extensive financial ties between researchers, FDA consultants, and pharmaceutical companies. For example, some committee members and investigators had multiple financial relationships with drug companies through paid lectures, research grants, and consulting fees.

9. Legal Implications

The author served as a medical expert in numerous product liability suits against pharmaceutical companies, with most cases being settled for significant amounts rather than going to trial. This suggests the pharmaceutical companies preferred to avoid public scrutiny of the evidence in court.

10. Violence and Suicide Reports

Multiple cases of violence, suicide attempts, and aggressive behavior were reported in connection with Prozac use, though these were not adequately captured in the initial trials due to the exclusion of at-risk populations and the short duration of studies.

11. Misleading Marketing

The book exposes how some researchers, like Dr. Fieve, made public claims about Prozac's efficacy that contradicted the actual trial results. Claims of 65-70% improvement rates were impossible given the high dropout rates and predominantly negative study results.

12. Scientific Independence

The book demonstrates the importance of independent scientific analysis, showing how researchers without ties to pharmaceutical companies can identify significant issues years before the medical establishment acknowledges them. This independence allows for more objective assessment of drug risks and benefits.

Prozac Approval (Lies and Manipulations)

Here is a list of lies and manipulations used to get Prozac approved, based on the book:

• Eli Lilly designed the Prozac studies to exclude patients with serious suicidal tendencies. This exclusion was part of the formal protocol of each study used for FDA approval in the United States.

• Hospitalized psychiatric patients were also excluded from nearly all of the studies, including every one that was used to approve the drug.

• There were no children or elderly adults in the Lilly-sponsored FDA studies of Prozac.

• Misleading totals were given for the number of patients tested in clinical trials. Prozac's drug label claims that over 11,000 patients took the drug in clinical trials. However, a closer look at the data shows that only 286 Prozac patients completed the four-, five-, or six-week trials used as the basis for FDA approval.

• The FDA approval process for Prozac overlooked the many studies that showed the drug was ineffective. As long as two or more studies show statistical superiority over a placebo, a drug can be approved. In the case of Prozac, there were more negative efforts than positive, but this made no difference in the approval process.

• The placebo-washout strategy was used in the Prozac studies. This technique (see Q6) removes patients who respond well to placebo from the study, making the drug appear more effective.

• Eli Lilly reshuffled data from Protocol 27 to make Prozac look more effective. When the initial results from this protocol showed Prozac to be ineffective, Lilly removed data from one of the studies, excluded patients who had received other psychiatric medications along with Prozac, and pooled the remaining data from five studies, treating them as if they belonged to one study.

• Eli Lilly published misleading results about Protocol 27. The published version of the study did not mention that the individual studies failed to show efficacy for Prozac, or that Prozac's performance was weak at best. Unlike the FDA analysis, which showed the older antidepressant Tofranil to be superior to Prozac, the Lilly version claimed Prozac to be as effective as Tofranil.

• One of the principal investigators, Ronald R. Fieve, made false claims about the efficacy of Prozac in his book Prozac: Questions and Answers for Patients, Family, and Physicians. He stated that Prozac was proven as effective as Tofranil, when Tofranil wasn't even included in the study. He also claimed that Prozac patients experienced a startling absence of side effects compared to imipramine patients, when, in fact, there were no imipramine patients for comparison. Fieve also claimed that up to 70 percent of patients would improve on Prozac, a figure that did not account for the high dropout rates in the study due to adverse effects and lack of efficacy.

• The inclusion of sedative drugs in Lilly’s approval studies distorted the results. In effect, the FDA ended up approving Prozac in combination with sedatives. Prozac failed to show significant efficacy when data from patients taking sedative drugs were removed from the pooled data.

• The FDA edited out the most significant and often-repeated observations and warnings of its own official reviewer, Richard Kapit. Kapit warned that Prozac acts like a stimulant and might worsen depression in some cases. However, these warnings were removed from the drug's label.

• The FDA’s system of codifying adverse drug reactions placed limitations on the usefulness of the data for evaluating Prozac’s potential to cause suicidal ideation and acts. Eli Lilly’s system also lacked categories for suicidal acts and suicidal ideation. When a doctor submitted an adverse drug reaction report to Lilly that included suicide or suicide ideation, Lilly listed it under something else.

• The FDA did find a disproportionately high number of spontaneous reports of Prozac-induced “hostility and intentional injury” during the first year of the drug’s marketing. However, this critical finding was mentioned only in passing and not investigated further.

• Many members of the FDA advisory committee that evaluated Prozac had financial ties to drug companies, including Eli Lilly.

• Eli Lilly intervened in the criminal justice system to discredit the “Prozac defense.” This strategy prevented the courts from recognizing that Prozac can cause violent and criminal behavior.

• Eli Lilly guaranteed to fund the defense of any physician who prescribed Prozac according to accepted practice. This was done to discourage malpractice suits against doctors who prescribe Prozac.

• Eli Lilly partnered with the National Institute of Mental Health (NIMH) to convince massive numbers of Americans that they suffer from depression. This was done through a media campaign that promoted the use of Prozac.

• Eli Lilly placed misleading ads for Prozac in medical journals. One ad implied that Prozac should be the first choice for treating nine different symptoms of depression.

These are just some of the lies and manipulations that were used to get Prozac approved. The book make it clear that the FDA approval process is heavily influenced by the pharmaceutical industry.

36 Questions & Answers

1. What was the actual number of patients who completed the FDA approval trials for Prozac? The grand total of patients who completed the four to six-week trials used for FDA approval was 286 patients. This number was culled from an original pool of thousands who started the trials, representing a remarkably small sample size for such a widely prescribed medication.

The limited number of completers is particularly striking given that the FDA based its approval on seventeen studies across three protocols. This small number of completing patients is not widely known among physicians or patients who rely on FDA studies, as most assume the testing pool is much larger.

2. How does the FDA's drug approval process actually work? The FDA does not conduct its own independent studies during the drug approval process, as they lack the funding to do so. Instead, all FDA drug studies are constructed, supervised, and paid for by the pharmaceutical companies themselves, using doctors and research teams of their own choosing - typically individuals with established relationships with the company.

The approval process only requires two or more studies showing statistical superiority over placebo, regardless of how many failed studies exist. In Prozac's case, fourteen protocols involving controlled studies were submitted, with only three showing beneficial effects while the majority demonstrated no positive effect.

3. What were the three protocols the FDA used to approve Prozac? Protocol 27 was one of the main protocols, initially involving more than 700 patients at six separate sites, though it ended with fewer than 150 Prozac patients remaining. The studies were run by different principal investigators, and ultimately only 104 patients completed the six-week trials in this protocol.

The other protocols faced similar attrition rates and complications. For example, in one protocol, only 25 patients finished the trials, with just 11 having been given Prozac. The trials required considerable statistical maneuvering to demonstrate positive results.

Long Term Effects

The book highlights several concerning long-term effects associated with Prozac use:

Neurological Disorders

Prozac may lead to various neurological disorders, similar to those caused by neuroleptic drugs:

• Parkinsonism symptoms, resembling those of Parkinson’s disease.

• Dystonia, characterized by painful and involuntary muscle spasms.

• Potential for permanent neurological disorders.

Brain Changes

Prolonged Prozac use raises significant concerns about permanent brain alterations:

• Serotonergic receptors may experience permanent down-regulation.

• Compensatory receptor changes can become irreversible after extended treatment.

• Long-term effects may include brain dysfunction, similar to how tardive dyskinesia results from dopaminergic receptor alterations.

Unknown Risks

The lack of research into long-term safety is a critical issue:

• No systematic studies exist on effects after stopping the drug.

• Most research focuses on short-term outcomes, ending soon after discontinuation.

• Persistent abnormalities have not been investigated by pharmaceutical companies or researchers.

• Long-term effects persisting for days, weeks, or months remain untested.

Physical Effects

Prozac use over time can lead to various physical complications:

• Blood vessel inflammation, such as vasculitis.

• Bleeding problems caused by disrupted serotonin uptake in blood platelets.

• Severe allergic reactions.

• Issues with sodium levels and water retention.

Conclusion

The book strongly criticizes psychiatrists who recommend lifetime Prozac use, arguing that such recommendations lack adequate research on long-term safety. It notes the medical establishment's history of delayed recognition of severe side effects from psychiatric medications.

4. Why were suicidal patients excluded from clinical trials? The clinical trials specifically excluded several major patient populations, including suicidal patients, hospitalized psychiatric patients, children, and elderly adults. This selective inclusion criteria meant that the drug's effects were only tested on a limited subset of the population.

This exclusion is particularly significant since the drug would later be prescribed to these excluded groups without proper testing. The trials' narrow focus on a specific patient demographic raises questions about the broader applicability of the results.

5. What was the typical duration of the controlled clinical trials? The scientifically controlled trials for Prozac lasted only four to six weeks, contrary to the common belief that FDA approval studies involve long-term testing. While some less scientifically rigorous projects extended beyond this timeframe, these were exceptions rather than the norm.

Statistical data shows that 86 percent of all patients in all studies were treated for three months or less. This short duration raises questions about the long-term effects and safety of the medication, as anyone taking Prozac for more than a few weeks effectively became part of an ongoing experiment on its longer-term effects.

6. What is the placebo-washout strategy and how did it affect results? The placebo-washout strategy is a technique used in drug studies where all patients are initially given a placebo for a period of time, typically one week. Those patients who show improvement on the placebo are then dropped from the study, and the trials are restarted with a placebo and a drug group. This technique is used to create a pool of patients who are less likely to respond to placebo, making it easier to demonstrate the efficacy of the drug being tested.

The placebo washout can make a drug seem more effective than it actually is. This is because patients who respond positively to the placebo might not have responded to the drug if they had received it in the second part of the testing. By removing these patients from the study, the results are skewed in favor of the drug. The placebo washout also reduces the total number of positive responders in both the placebo and drug groups, which makes any difference between the two groups statistically more significant. This technique was used in the FDA approval process for Prozac, and it is likely that it contributed to the drug's approval, despite the fact that many individual studies failed to show efficacy.

Criticisms of Prozac

The book outlines several major criticisms of Prozac, which are organized into key categories:

Safety and Side Effects

Prozac exhibits a concerning stimulant profile, with reported side effects including:

• Nervousness (14.9%)

• Insomnia (13.8%)

• Anxiety (9.4%)

• Significant weight loss (13%) Additionally, the drug can trigger severe conditions such as mania, akathisia (affecting 15-25% of patients), and various neurological disorders.

Clinical Trial Issues

The FDA approval process faced significant criticism:

• Trials were conducted on a highly selective patient population, excluding suicidal individuals, hospitalized psychiatric patients, children, and elderly adults.

• Many trial participants were concurrently using additional medications, such as sedatives, obscuring Prozac's true effectiveness and side effect profile.

Behavioral and Mental Health Concerns

Prozac may exacerbate mental health issues and contribute to:

• Agitation and restlessness

• Mania or hypomania

• Paranoia, potentially leading to violent behavior

• Obsessive-compulsive thoughts

• Sexual dysfunction

Drug Interactions

Prozac poses risks of dangerous interactions with other medications by:

• Increasing the toxicity of lithium and tranquilizers

• Elevating blood concentrations of anticoagulants and cardiac drugs

• Amplifying neuroleptic effects when combined with medications like Thorazine

Misrepresentation of Effects

The book alleges that Prozac’s adverse effects were underreported and misrepresented. For instance:

• Sexual dysfunction rates were split into multiple categories in official labeling, obscuring the overall prevalence of the issue.

Conclusion

The book criticizes Prozac for its stimulant-like effects, inadequately tested safety, and the underreporting of adverse effects. It highlights systemic issues in the approval and representation of the drug, emphasizing its potential to harm vulnerable populations.

7. How were the double-blind controlled studies constructed? A typical protocol required randomly dividing depressed patients into two sections - one receiving placebo and one receiving Prozac for four to six weeks. Some protocols divided participants into three groups, with the third group receiving an older, proven antidepressant for comparison purposes.

The studies utilized various tests to evaluate week-by-week improvement, including self-assessment and brief interviews with professionals who checked off symptom lists. No intensive interviews were utilized, and each study was directed by a principal investigator selected by Eli Lilly to ensure the project followed the company's protocols.

8. What role did sedative medications play in the trial results? About one-third of the patients in the trials received additional psychiatric medications, including minor tranquilizers and sedatives, alongside Prozac. This concurrent use of multiple medications made it impossible to determine whether any positive results could be attributed to Prozac alone.

The FDA effectively approved Prozac in combination with sedatives, as the inclusion of these additional medications complicated the interpretation of results. This mixing of medications raises questions about the true efficacy of Prozac as a standalone treatment.

9. What percentage of patients dropped out of clinical trials early? The dropout rates in the Prozac trials were substantial, with some studies losing up to 50% of their initial participants. In Protocol 27, for example, from an initial group of more than 700 patients, fewer than 150 Prozac patients remained by the end of the trial.

The high attrition rates significantly impacted the studies' statistical power and reliability. In some cases, researchers even included partial data from patients who didn't complete the trials in their statistical analyses to achieve positive results.

Violent Behaviour

The book identifies several mechanisms linking Prozac to violent behavior, organized into distinct categories:

Drug-Induced Disorders

Prozac can cause three primary drug-induced disorders associated with violent behavior:

• Agitation and Anxiety: Can lead to desperation and heightened irritability.

• Mania: Triggers hostile, erratic, and uncontrollable behavior.

• Akathisia: A neurological disorder causing intense inner tension and compulsive movements, linked to aggression.

Psychological Effects

The drug may induce psychological changes that heighten the risk of violence:

• Paranoia: Leads to irrational fears and blame-shifting.

• Obsessive-Compulsive Thoughts: Intrusive thoughts focused on death or violence.

• Personality Changes: Includes emotional detachment and loss of empathy.

• Depression Mimicry: Symptoms resembling or exacerbating depression.

Stimulant Properties

Prozac’s stimulant-like effects may enable violent impulses:

• Increased Energy: Can facilitate acting on destructive urges.

• Insomnia and Restlessness: Aggravates irritability and impulsivity.

• Nervousness: Affects 14.9% of patients, contributing to agitation.

• Anxiety: Experienced by 9.4% of patients, intensifying emotional instability.

Documented Cases

The book references numerous incidents illustrating these links:

• A ten-year-old boy became hyperactive, agitated, and issued death threats.

• A teacher fatally stabbed his estranged wife.

• A 76-year-old woman shot her husband in his sleep.

• Various cases of domestic violence and murder occurred shortly after patients began Prozac or increased their dosage.

Biological Mechanism

Prozac’s influence on neurotransmitter systems may facilitate violent behavior:

• Serotonergic Stimulation: Alters emotional regulation and behavior.

• Dopamine Suppression in the Frontal Lobes: Impairs impulse control.

• "Robot-Like" State: Reduces emotional responsiveness and self-regulation.

Conclusion

The book argues that Prozac’s complex interplay of neurological and psychological effects can create conditions where previously non-violent individuals may engage in aggressive or violent actions, often without apparent explanation.

10. How did the inclusion/exclusion criteria affect trial outcomes? The strict inclusion/exclusion criteria resulted in a highly selective patient population that didn't represent the full spectrum of people who would eventually receive Prozac prescriptions. The trials excluded hospitalized psychiatric patients, children, elderly adults, and suicidal patients, creating a significant gap between the test population and real-world usage.

This selective approach to patient inclusion meant that the drug's effects were only tested on a limited population, though it would later be prescribed to many of the excluded groups. The narrow focus of the trials raises questions about the broader applicability of the results to the general population.

11. What criticisms did the FDA make of Dr. Feighner's research practices? The FDA's investigation revealed significant protocol violations at Dr. Feighner's research site. In an April 1984 memo by Walter Sloboda, a psychologist in the Division of Scientific Investigation, it was discovered that a patient was mistakenly given both Prozac and Tofranil simultaneously, and this error had not been properly recorded. The investigation also found that abnormal laboratory findings were not properly documented.

Frances O. Kelsey, Ph.D., M.D., Director of the Division of Scientific Investigation, later sent a letter on August 7, 1984, citing "several departures from Food and Drug Administration regulations or commonly accepted drug investigational practices." The letter emphasized Feighner's need to follow proper inclusion and exclusion criteria, though he agreed with these observations and promised to remedy them.

12. What were the specific concerns about Dr. Fabre's studies? According to the FDA's critical analysis from their in-house meeting, Dr. Fabre's study had significant duration issues. While the trial was planned for five weeks, the FDA found that Fabre actually had only a 4-week trial at most, making it shorter than the required protocol length.

The study's completion numbers were remarkably low, with only 25 patients finishing the trials, of which just 11 had been given Prozac. Despite these serious limitations and the need for considerable statistical maneuvering to show positive results, the study surprisingly became one of the cornerstones for approving Prozac.

Addiction

Peter Breggin's Talking Back to Prozac, strongly suggest that Prozac has the potential for addiction and abuse, despite claims to the contrary by Eli Lilly and the FDA.

Breggin draws parallels between Prozac and classic stimulants like amphetamines and cocaine, highlighting their shared stimulant profile, including increased energy, euphoria, and potential for withdrawal symptoms. He notes anecdotal reports of Prozac abuse, including injecting the drug, obtaining it illicitly, and using it to achieve a high. Breggin also cites research evidence that demonstrates Prozac's ability to substitute for amphetamines in animal studies, suggesting a similar potential for dependence and abuse in humans. He criticizes the FDA's inadequate investigation into Prozac's addictive potential, pointing to their failure to systematically test for dependence, abuse, and withdrawal during the approval process.

Furthermore, Breggin argues that the FDA's historical failure to recognize the addictive qualities of other prescription medications, like Valium and Darvon, underscores their potential to misjudge the risks associated with Prozac. The sources raise significant concerns about the potential for Prozac addiction, particularly given the FDA's documented shortcomings in investigating this issue and their tendency to prioritize the interests of pharmaceutical companies over patient safety.

13. How did the FDA handle protocol violations during trials? The FDA appeared to take a relatively lenient approach to protocol violations. In Protocol 62, for example, patients were supposed to be excluded if they took any additional drug except chloral hydrate. However, in actual practice, patients were not excluded even when they took benzodiazepines, directly violating the protocol requirements.

Despite finding numerous violations across multiple studies, the FDA often allowed the data to be included in the final analysis. This approach was evident in their handling of protocol amendments and their willingness to accept pooled data from studies with documented violations, suggesting a pattern of flexibility in enforcing protocol requirements.

14. What role did informed consent play in the studies? Informed consent issues were identified in several studies, with some investigators failing to properly document patient consent. In one notable case, Dr. Cohn had failed to obtain written informed consent and was found to have backdated consent forms, leading to serious concerns about the ethical conduct of the trials.

The FDA's investigation revealed multiple instances where proper informed consent procedures were not followed, particularly regarding the documentation of patient histories and conditions. This included cases where investigators failed to indicate important patient medical history, such as alcoholism and liver conditions, which should have been disclosed as part of the informed consent process.

15. How were adverse events reported and tracked? FDA psychiatrist Richard Kapit wrote the official Safety Review of adverse reactions, drawing on Lilly-sponsored studies and general information sources. His report, obtained through the Freedom of Information Act, detailed the type, frequency, and severity of negative drug effects.

In his analysis, Kapit noted that the most frequent adverse effects were nausea, insomnia, and nervousness, which created a profile more similar to a stimulant than a sedative drug. The reporting system identified these as the "greatest clinical liabilities" in the medication's use, along with additional effects like anorexia and weight loss.

16. How many patients were initially enrolled versus completed the studies? In Protocol 27 alone, more than 700 patients were initially enrolled at six separate sites. However, by the completion of the protocol, and after excluding data from one site, fewer than 150 Prozac patients remained, with only 104 completing the six-week trials.

The dramatic reduction in patient numbers was a pattern across multiple protocols. For example, in one protocol, from an initial group of participants, only 25 patients finished the trials, with just 11 having received Prozac. This high attrition rate significantly impacted the statistical validity of the results.

17. What statistical manipulations were questioned by the FDA? The FDA questioned Lilly's practice of pooling data from separate negative studies to achieve positive overall results. In Protocol 27, after initial negative results, Lilly reshuffled the data by removing some but not all of Cohn's data, excluded patients who had received other psychiatric medications, and then pooled the remaining data from five studies into one batch for statistical analysis.

This manipulation increased the total number of subjects for analysis, making it easier to demonstrate statistical significance for relatively minor improvements. The FDA's March 28, 1985, efficacy review noted that these results were not convincing, stating that while imipramine was clearly more effective than placebo, fluoxetine was less consistently better.

18. How were efficacy measurements determined? Efficacy measurements were primarily based on comparing Prozac to both placebo and existing antidepressants like imipramine (Tofranil). The studies utilized various tests to evaluate week-by-week improvement, including patient self-assessments and brief interviews with professionals who checked off symptom lists.

The FDA required that a new drug must prove its efficacy in double-blind controlled studies. However, in many cases, the efficacy measurements were complicated by factors such as the inclusion of patients taking additional medications and the high dropout rates, which required various statistical adjustments to demonstrate positive results.

19. What was the significance of the "pooled data" analysis? The pooled data analysis became a controversial aspect of Prozac's approval process. When individual studies failed to show significant results, Lilly combined data from multiple studies to increase the statistical power. This was particularly evident in Protocol 27, where data from five studies was pooled after removing certain negative results.

The FDA's acceptance of pooled data analysis was crucial for Prozac's approval, despite concerns about its validity. When Lilly resubmitted calculations excluding Cohn's data (which eliminated 25% of the total protocol patients) and reincluded patients who had taken additional psychiatric drugs, they finally achieved positive results on four measurements of improvement.

20. How were multiple-drug interactions analyzed in the studies? The analysis of multiple-drug interactions was problematic throughout the trials. Approximately one-third of patients received additional psychiatric medications, including minor tranquilizers and sedatives, alongside Prozac. This made it impossible to determine whether positive results could be attributed to Prozac alone.

Notably, when patients taking sedative drugs were removed from the pooled data, Prozac failed to show significant efficacy. The drug only proved efficacious when patients taking additional sedative drugs were reincluded in the analysis, effectively meaning the FDA approved Prozac in combination with sedatives rather than as a standalone treatment.

21. Who were the principal investigators in Protocol 62? Protocol 62 involved multiple investigators across ten centers, though specific details about individual investigators are limited. The protocol started with approximately 900 patients but faced significant attrition rates throughout the study period, similar to other protocols.

The investigators were selected by Eli Lilly and were typically doctors with established relationships with the company. This selection process raised questions about potential conflicts of interest, as many investigators had ongoing financial relationships with pharmaceutical companies.

22. What was Columbia University's role in the trials? Michael E. Stanley, Ph.D., professor of clinical psychopharmacology at Columbia's College of Physicians and Surgeons, played a significant role as an FDA consultant during the hearings. His involvement was particularly noteworthy because he simultaneously maintained substantial financial ties to Eli Lilly.

At the time of the FDA hearing, Stanley was being paid $26,250 by Eli Lilly to write a paper examining the possible relationship between suicidal behavior, treatment with antidepressants, and serotonergic activity - the very subject of the hearing.

23. How were research centers selected for the studies? Research centers were chosen primarily through Eli Lilly's existing network of investigators and research facilities. The company selected doctors and research teams with whom they had established relationships, often those who had previously conducted trials for them or other pharmaceutical companies.

The selection process appeared to favor centers and investigators who had proven track records of completing drug trials, though this approach raised concerns about potential bias. Many of the selected investigators had ongoing financial relationships with pharmaceutical companies through grants, consulting fees, and speaking engagements.

24. What conflicts of interest emerged during the trials? Multiple conflicts of interest surfaced during the trials and subsequent hearings. For example, David Dunner from the University of Washington Medical Center had $500,000 worth of drug company grants under his supervision and an additional $200,000 in pending grants from Eli Lilly at the time of the FDA hearing.

Committee members and investigators often had multiple financial ties to pharmaceutical companies, including paid lectures, research grants, and consulting fees. These relationships raised serious questions about the objectivity of the trial process and subsequent FDA review.

25. How did different investigators' results compare? The results varied significantly among different investigators. Some sites reported positive outcomes while others showed no beneficial effects. For example, Dr. Cohn's data was eventually excluded from Protocol 27, eliminating 25% of the total protocol patients.

These variations led to controversial statistical manipulations, including the pooling of data from multiple studies to achieve positive results. The inconsistencies between different investigators' findings raised questions about the reliability and reproducibility of the trial results.

26. How did results differ between mildly and moderately depressed patients? The trials primarily focused on outpatients with moderate depression, as severely depressed and suicidal patients were excluded from the studies. This selective inclusion criteria made it difficult to determine how the drug would affect patients with varying degrees of depression.

The limited scope of the patient population studied meant that there was insufficient data to make meaningful comparisons between mild and moderate depression cases. This gap in the research would later become significant as the drug was prescribed to patients across the full spectrum of depression severity.

27. What percentage of patients received additional medications? Approximately one-third of patients in the trials received additional psychiatric medications, including minor tranquilizers and sedatives, alongside Prozac. This widespread use of concurrent medications complicated the interpretation of the trial results.

The inclusion of patients taking multiple medications made it impossible to determine whether positive results could be attributed to Prozac alone. When patients taking sedative drugs were removed from the pooled data, Prozac failed to show significant efficacy.

28. How were adverse reactions documented and analyzed? FDA psychiatrist Richard Kapit wrote the official Safety Review of adverse reactions, drawing on Lilly-sponsored studies and general information sources. The review documented the type, frequency, and severity of negative drug effects through a standardized reporting system.

The most frequently reported adverse effects were nausea, insomnia, and nervousness, creating a profile more similar to a stimulant than a sedative drug. However, concerns were raised about the thoroughness of adverse event reporting, particularly regarding more serious effects.

29. What were the dropout rates across different protocols? Dropout rates were consistently high across all protocols. In Protocol 27, from an initial group of more than 700 patients, fewer than 150 Prozac patients remained by the end of the trial, with only 104 completing the six-week trials.

Similar patterns emerged in other protocols. For example, one protocol ended with only 25 patients completing the trials, of which just 11 had received Prozac. These high attrition rates significantly impacted the statistical validity of the results.

30. How were patient improvements measured? Patient improvements were evaluated through a combination of self-assessments and brief interviews with professionals who checked off symptom lists. The studies utilized various standardized tests to evaluate week-by-week improvement.

No intensive interviews were utilized in the measurement process. Instead, the focus was on quantifiable metrics that could be easily compared across different study sites. This approach raised questions about the depth and quality of the improvement assessments, particularly given the complex nature of depression symptoms.

31. What was the GAO's role in investigating FDA practices? The Government Accountability Office (GAO), a congressional watchdog agency, investigated the FDA's postmarketing surveillance of adverse drug reactions in April 1990. The GAO's investigation found that out of 198 drugs approved by the FDA between 1976 and 1985, 102 (more than half) had serious postmarketing risks that required labeling changes. Six of the drugs were no longer approved. **The GAO noted that it could take the FDA several years to act on postmarketing risks. ** This investigation highlighted the limitations of the FDA's reliance on voluntary reports from physicians to detect problems with approved drugs. The GAO also criticized the FDA's emphasis on the initial drug approval process, which resulted in inadequate long-term monitoring of adverse drug reactions.

The GAO's investigation provided further evidence that the FDA's drug approval process was not effectively protecting consumers from harmful drugs. The findings of this investigation are consistent with Peter Breggin's argument in Talking Back to Prozac that the FDA is too heavily influenced by the pharmaceutical industry and does not adequately prioritize consumer safety. The GAO's work, along with the work of other critics like Breggin, has helped to bring about some reforms at the FDA, but many problems remain.

32. How did the FDA handle protocol amendments? The FDA showed considerable flexibility in accepting protocol amendments and changes. When Eli Lilly reworked their data submissions, the FDA accepted major modifications, including the exclusion of entire data sets and the reincorporation of patients who had taken additional psychiatric medications.

The agency demonstrated this flexibility particularly in Protocol 27, where they accepted Lilly's decision to exclude all of Cohn's data (which eliminated 25% of the total protocol patients) and allowed the reincorporation of patients who had taken additional psychiatric drugs during trials.

33. What documentation protocol violations occurred? The sources provide several examples of protocol changes and violations during the FDA trials for Prozac.

For example, during an FDA investigation of Protocol 27, a psychologist in the Division of Scientific Investigation noted several violations in a memo, including the fact that a patient was mistakenly given Prozac in addition to Tofranil. This error was not properly recorded. The FDA also found that Dr. Feighner, the principal investigator, failed to follow the inclusion and exclusion criteria of the study. In another example, the FDA criticized Dr. Abuzzahab, a principal investigator in Protocol 27 and 62, for not adhering to the protocols and for failing to give proper notification when making protocol changes. The sources do not state what, if any, documentation was provided by Feighner or Abuzzahab.

The minutes from the FDA's "In-House Meeting on Fluoxetine" indicate that the FDA was aware of a major flaw in the "experimental design and execution" of the Prozac studies, particularly those testing efficacy. This flaw involved breaking the "double-blind" in the studies by switching patients who were not doing well to Prozac, regardless of whether they were initially assigned to the placebo or the control drug. The minutes do not mention any documentation for this change, but they do show that the FDA allowed Lilly to continue with the flawed protocols. This suggests that documentation requirements may have been lax or inconsistently applied during the Prozac trials.

34. What role did the Freedom of Information Act play? The Freedom of Information Act played a crucial role in allowing access to the FDA's internal documents and reviews of Prozac. Through FOIA requests, researchers were able to examine each of the seventeen studies used for FDA approval.

The Act enabled access to critical documentation, including the FDA psychiatrist Richard Kapit's official Safety Review of adverse reactions, which provided detailed information about the type, frequency, and severity of negative drug effects.

35. How did the short duration of trials affect long-term safety assessment? The scientifically controlled trials lasted only four to six weeks, which severely limited the ability to assess long-term safety. While some less rigorous projects extended beyond this timeframe, 86 percent of all patients in all studies were treated for three months or less.

This short duration meant that anyone taking Prozac for more than a few weeks effectively became part of an ongoing experiment on its longer-term effects. The brief trial period made it impossible to evaluate the drug's long-term safety profile or chronic side effects.

36. How did real-world usage differ from clinical trial conditions? The clinical trials excluded several major patient populations, including suicidal patients, hospitalized psychiatric patients, children, and elderly adults. This selective inclusion criteria meant that the drug's effects were only tested on a limited subset of the population who would eventually receive prescriptions.

The trials also involved concurrent use of other medications, particularly sedatives, which complicated the interpretation of results. Approximately one-third of patients received additional psychiatric medications during the trials, making it impossible to determine whether positive results could be attributed to Prozac alone.

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