Conflicts of interest Peter C Gøtzsche Director and Professor Nordic Cochrane Centre I have no conflicts of interest
Slide from Whitaker, author of Mad in America and Anatomy of an Epidemic
ADHD It’s just a name, not a biological entity The diagnosis arises primarily from teacher complaints Many of us could get this diagnosis 11% of school-age children in the United States have it
ADHD drugs, acute effects ADHD drugs work like amphetamine and cocaine The major effect of stimulants appears to be an improvement in classroom manageability rather than academic performance Reductions in social interactions and curiosity
ADHD drugs, long-term effects Stimulants do not produce lasting improvements in: - aggressivity - conduct disorder - criminality - education achievement - job functioning - marital relationships - or long-term adjustment American Psychiatric Association’s Textbook of Psychiatry, 1994
ADHD drugs, long-term effects Long-lasting brain damage in animal studies: - anxiety - depression - loss of sexual interest - less tolerance to stress - decreased sensitivity to rewards Source: S. Castner. “Long-lasting psychotomimetic consequences of repeated low-dose amphetamine exposure in rhesus monkeys,” Neuropsychopharmacology 20 (1999):10-28; E. Marco, “Neurobehavioral adaptations to methylphenidate,” Neuroscience and Behavioral Reviews 35 (2011):1722-1739. W. Carlezon, “Enduring behavioral effects of early exposure to methylphenidate in rats,” Biological Psychiatry 54 (2003):1330-37; C. Bolanos, “Methylphenidate treatment during pre-and periadolescence alters behavioral responses to emotional stimuli at adulthood,” Biological Psychiatry 54(2003):1317-29. Slide adapted from Whitaker, author of Mad in America and Anatomy of an Epidemic
Slide from Whitaker, author of Mad in America and Anatomy of an Epidemic
Antidepressants, any benefits? 2006 FDA analysis of 100,000 patients in placebo controlled trials: - only 4% on active drug got tricyclics - half of the patients had depression - 50% responded on drug, 40% on placebo - the 40% is NOT a placebo effect! Cochrane review of depression in general practice: - 58% responded on drug, 46% on placebo - biased estimate: based on published trials in contrast to FDA analysis www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4272b1-01-FDA.pdf Arrol CD007954
Spontaneous improvement is commonLundbeck meta-analysis of 3 trials, scale goes from 0 to 60 • Gøtzsche PC. Deadly medicines and organised crime (the difference between the two drugs is not reliable)
Antidepressants, any benefits? The effect is measured on highly subjective scales, e.g. Hamilton. Systematic review of 21 trials in a variety of disease areas that had both blinded and nonblinded outcome assessors. Most trials had used subjective outcomes. The effect was exaggerated by 36% on average (measured as odds ratio) by the nonblinded observers. What if the blinding has been broken for all patients? The 10% difference in effect becomes zero (odds ratio 1.02) Hróbjartsson et al, BMJ 2012;344:e1119.
Antidepressants, any benefits? Cochrane review with an active placebo (atropine) - 9 trials, 751 patients - tricyclic antidepressants - one trial had an implausibly large effect - omitting this trial, the SMD was 0.17 - this corresponds to 1.3 on the Hamilton 17 scale, i.e. no effect (as median SD after treatment was 7.5 in 11 placebo-controlled trials with 37 arms; clinical study reports of SSRIs in our possession) - included studies: 7 from 1961-66, 2 from 1970s, 1 from 1984 Moncrieff et al, Cochrane review;CD003012.
Antidepressants, any benefits? Considering benefits and harms together, the patients find the drugs useless: - as many patients stop treatment on SSRIs as on placebo for any reason. - after only 2 months, half the patients have stopped taking the drug. And so did the psychiatrists and the drug regulators in the beginning: - the first SSRI was fluoxetine, which the German drug regulator deemed “totally unsuitable for the treatment of depression”. - fluoxetine was approved in Sweden first, through bribery. Barbui, CMAJ 2008;178:296; Serna, Eur Psychiatry2010;25:206; Gøtzsche PC. Deadly medicines and organised crime; Virapen J. Side Effects: death. College Station: Virtualbookworm.com Publishing;2010.
Antidepressants, any benefits? It seems likely to me that antidepressants don’t work. Many patients and doctors think they work but they forget about the natural cause of the depression. Do they have any meaningful effect on outcomes that matter, e.g. saving relationships and getting people back to work? They cause sexual problems in half of those treated and who did not have problems before they were treated. Is it likely that they help saving intimate relationships? Montejo, J Clin Psychiatry 2001;62(Suppl. 3):10–21.
Antidepressants, any harms?UK labelling for citalopram, 52 pages (rare events omitted)
Sexualdisturbances An FDA scientist found out that the companies had hidden sexual problems by blaming the patients rather than the drug, e.g. female anorgasmia was coded as ‘Female Genital Disorder’ The companies: only 5% of the patients become sexually disturbed Independent research: 59% of 1022 people with a normal sex life became sexually disturbed, with a low tolerance among 40% of the patients: - decreased libido, 50% of patients on fluoxetine, - delayed orgasm or ejaculation, 50% - no orgasm or ejaculation, 39% - erectile dysfunction or decreased vaginal lubrication ,22% Some patients yawned during orgasm Gøtzsche PC. Deadly medicines and organised crime: How big pharma has corrupted health care. London: Radcliffe Publishing, 2013. Montejo et al., J Clin Psychiatry. 2001; 62(Suppl. 3):10–21.
Withdrawal symptoms Not listed in table of side effects in UK packageinsert for citalopram but in the text: “In clinical trials adverse events seen on treatment discontinuation occurred in approximately 40% of patients treated with citalopram. ”recommended that the dose is gradually reduced over a period of at least one week” Most symptoms that occur after abrupt withdrawal aren’t depression symptoms but symptoms of abstinence. When slow tapering of SSRIs was attempted after successful behavioural treatment for panic disorder and agoraphobia, which is not depression, about half of the patients had withdrawal symptoms. Gøtzsche PC. Deadly medicines and organised crime: How big pharma has corrupted health care. London: Radcliffe Publishing, 2013. Fava et al., Int J Neuropsychopharmacol. 2007; 10: 835–8.
Withdrawal symptoms The withdrawal symptoms were described in similar terms for benzodiazepines and SSRIs and were very similar for 37 of 42 identified symptoms. However, they were not described as dependence for SSRIs. To define similar problems as “dependence” for benzodiazepines and as “withdrawal reactions” for SSRIs is irrational. For patients, the symptoms are just the same; it can be very hard for them to stop either type of drug. Nielsen, Addiction 2012;107:900; Gøtzsche PC. Deadly medicines and organised crime;
The chemicalimbalancehoax Abouthalf the patients (or more) have been told: “You have a 'chemical imbalance’ in the brain, which we will need to fix.” “This is like giving insulin to a patient with diabetes .” If this were true, the number of disabled mentally ill would have gone down after we introduced antipsychotics and antidepressants, but instead, the number of people with psychiatric diagnoses and disability pension has skyrocketed. The drugs CREATE a ’chemicalimbalance’, which is why it is so difficultstoppingthem. In contrast to insulin, the drugs aretotallyunspecific and theymaketemporary problems chronic. Whitaker R. Anatomy of an Epidemic. New York: Broadway Paperbacks; 2010 and various surveys.
Antidepressants and suicide FDA analysis: Antidepressants increase suicidal behaviour till age 40 www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4272b1-01-FDA.pdf
When the FDA publishedtheirfindings, theylookedmuchbetter for the drug companies Antidepressants and suicide Stone et al., BMJ 2009;339:b2880
Antidepressants and suicide Suicide risk is far worse than what the FDA found many suicides and suicide attempts were missing, e.g. 5 suicides in 52,960 patients on antidepressants in the FDA analysis 5 suicides in 2,963 patients on paroxetine in a 1993 meta-analysis Only events occurring within 24 hours after stopping drug were included. People with agitation/akathisia were put on benzodiazepines. Gøtzsche PC. Deadly medicines and organised crime: How big pharma has corrupted health care. London: Radcliffe Publishing, 2013
Antidepressants and suicide Suicide risk is far worse than what the FDA found Many suicidal events had been coded as something else, and the companies knew that the FDA would not check them when the FDA asked for their data. Some trials had run-in periods on active drug. Only people at very low risk of committing suicide were recruited for the trials. Gøtzsche PC. Deadly medicines and organised crime: How big pharma has corrupted health care. London: Radcliffe Publishing, 2013
Two flaws in antidepressant trials wash-outperiod randomisation treatment Patients in treatment placebo Events aftertreatment areignored
Example: sertraline studies in adults, suicides and suicide attempts FDA: suicide, suicide attempt or self harm (Laughren, see ref. in other slides) Pfizer: the same definitions (Vanderburg, J Clin Psychiatry 2009;70:674) Gunnell: suicide or non-fatal self harm (BMJ 2005;330: 19 Feb)
Fraud Suicides and attempts were also added to placebo after stopping active treatment Healy, BMJ 2006; 333:92–5
Antidepressants, suicide and falls Middle-aged people who were completely normal before they started on an SSRI and were not depressed or sad have also committed suicide (or homicide). A carefully controlled cohort study of depressed people over 65 years of age showed that SSRIs lead to falls. For every 28 elderly people treated for 1 year with an SSRI, there was one additional death, compared to no treatment. It is doubtful whether these drugs are safe at any age. ”Keep out of reach of children” Coupland et al, BMJ 2011;343:d4551.
Antidepressants and homicide Antidepressants can lead to violent actions at any age, including suicide and homicide. Gøtzsche PC. Deadly medicines and organised crime: How big pharma has corrupted health care. London: Radcliffe Publishing, 2013. Lucrire, Pharmgenomics Pers Med 2011; 4: 65–81.
Antidepressants and homicideAntidepressantscanlead to suicide and homicide at any age 10 Peoplewith CYTP450 mutations Lucrire, PharmgenomicsPers Med 2011; 4: 65–81. Gøtzsche PC. Deadly medicines and organised crime: How big pharma has corrupted health care. London: Radcliffe Publishing, 2013
All 10 people were able to stop taking antidepressants and return to their previously normal personalities Lucrire, PharmgenomicsPers Med 2011; 4: 65–81.
The fatal flaw in maintenance studies randomisation continuedtreatment Patients treated succesfully placebo Withdrawal symptoms in the placebo group areinterpreted as disease symptoms
Long-term results of maintenance trial • - 128 remitted first-episode psychotic patients • - randomized to dose reduction/discontinuation or maintenance for 2 years, thereafter Tx as decided by the clinicians • - 103 patients were located 7 years after randomisation • 2 yr 7 yr • Relapse 43% DR vs 21% M 62% DR vs 69% M • Recovery (main outcome) 40% DR vs 18% M • Dose in last 2 years was 64% higher in maintenance group • Stopped drug completely at 7 years: 11 versus 6 patients • Wunderink et al., JAMA Psychiatry. doi:10.1001/jamapsychiatry.2013.19
A couple of interesting facts Adverse drug events submitted to the FDA between 2004 and 2009 1937 cases of violence, 387 of which were homicide. The violence was particularly often reported for psychotropic drugs (antidepressants, sedatives/hypnotics, ADHD drugs and a smoking cessation drug that also affects brain functions). Until 2003, the UK drug regulator said that SSRIs are not addictive In 2003, the WHO published a report that noted that three SSRIs (fluoxetine, paroxetine and sertraline) were among the top 30 highest- ranking drugs for which drug dependence had ever been reported. In 2003, Glaxo quietly and in small print revised its previous estimate of the risk of withdrawal reactions in the prescribing instructions from 0.2% to 25%, a 100 times increase. Gøtzsche PC. Deadly medicines and organised crime: How big pharma has corrupted health care. London: Radcliffe Publishing, 2013 Moore et al, PLoS One 2010; 5: e15337. Medawar C, Hardon A. Medicines out of Control? Antidepressants and the conspiracy of goodwill. Netherlands: Aksant Academic Publishers; 2004.
Don’t ever trust published trials! • Publication bias, Eyding, IQWiG, BMJ 2010:c4737Data on 74% (3033/4098) of patients were unpublished
Ecological studies of suicide Many studies have claimed that when sales went down, suicides went up, and that this association is causal, e.g studies by: Robert Gibbons, Göran Isacsson, Christine Lu (BMJ 2014;348:g3596) These studies have numerous flaws. No sound studies have found this. Claims often based on the 2004 FDA black box warning in 2004 against suicide risk with SSRIs in children and in 2007 in adolescents: “We briefly summarize here five readily available, online data sources that provide more direct and valid measures of youth suicidal behavior, and we discuss problems with the proxy that Lu’s study used [poisonings by psychotropics] ... Lu’s study findings are roundly unsupported by national data” (Miller BMJ 2014;348:g3596) Gøtzsche PC. Deadly medicines and organised crime: How big pharma has corrupted health care. London: Radcliffe Publishing, 2013
Critics of antidepressant critics Probably the most common criticism of depression critics is that they are ignorant. It is often asserted that depression critics are callous towards people with depression, trivialising their suffering and their needs. Melissa Raven’s PhD, University of Wollongong, Australia, 2012 Nutt and two of his co-authors, Guy M Goodwin and Stephen Lawrie, have between them declared 22 confl icts of interest in relation to drug companies. I wonder whether this declaration explains their dismissal of psychotherapy (although it is effective and recommended by NICE) and their description of my evidence-based views as a somewhat irrational polemic that is insulting to the discipline of psychiatry and is reinforcing stigma against mental illnesses. They also talk about anti-psychiatry, anticapitalism, and a conspiracy theory. This is the language of people who are short of arguments. Gøtzsche PC, Lancet Psychiatry 2014;1:104-6
Evergreening and industry biasescitalopram verus citalopram Alkhafaji et al., BMC Medicine 2012, 10:142
Shift from benzodiazepines to antidepressants is not evidence-based(but not a good systematic review either) • Panic disorder, 11 trials of benzos against tricyclics • - fewer attacks: RR = 1.13; 95% CI = 1.01–1.27. • - fewer discontinuations: RR = 0.40; 95% CI = 0.20–0.57. • - less side effects: RR = 0.41; 95% CI = 0.34–0.50. • Newer antidepressants, only 3 trials • - comparable or greater improvements and fewer adverse events in patients suffering from generalised anxiety disorder or panic disorder Offidani et al., Psychother Psychosom 2013;82:355