New Drugs, New Problems

REPRINTED FROM THE AUSTRALIAN JOURNAL OF FORENSIC SCIENCES. 37:1 9-25, 2005.

INTRODUCTION

The Antidepressant Era, from 1988 to the present, may go down in history as a public health disaster. By conservative estimates, the “second generation” of antidepressants, in particular the(SSRIs) cause some 400 deaths a year in Australia from induction of suicide. They all have a similar profile for the induction of violence, with the more energising newer ones more heavily implicated. Clinical trials presented to the United States Food and Drug Administration (FDA) and other studies found that they produced a significant risk of suicide. The atypical antipsychotics produce more deaths again from suicide, and cardiovascular events. The drugs of concern are Prozac (fluoxetine), Zoloft (Sertraline), Aropax (paroxetine), Luvox (fluvoxamine), Cipramil (citalopram), Lexapro (escitalopram), Zyban, (bupropion), Efexor (venlafaxine) and Serzone (nefazodone), now withdrawn and others. The antipsychotics include Zyprexa (olanzapine) and Risperdal (risperidone) Seroquel (quetiapine) some others.

Psychiatric drugs are not alone in causing morbidity. In the United States, the fourth highest cause of death after heart disease, cancer and strokes are the adverse drug reactions. They are responsible for over 105,000 deaths per year and affect many more with their sublethal side effects.[i] If one adds improperly prescribed drugs and those taken incorrectly, adverse drug events (ADEs) become the third highest cause of death. A score of drugs licensed by the FDA in the 1990s have been withdrawn for lethal side effects that were noted in clinical trials but not disclosed to prescribers or patients. The recent withdrawal of Vioxx followed thousands of heart attacks and deaths. It was defended as ‘safe’ until two weeks before its withdrawal.[ii]

The term PhaRMA comes from the initials of the Pharmaceutical Research and Manufacturers of America. As part of their marketing they promote the medicalisation of stress. They encourage moral entrepreneurs of health who seek to bring all manner of distress into the province of psychiatry. They provide funds to political parties, medical journals and conferences to disseminate the kind of knowledge that suits their purposes, which are commercial and not altruistic. The increasing volume of information about the unintended consequences of the substances they sell brings home the need for a high level inquiry into the inducements offered by “Big PhaRMA” and the corresponding conflicts of interest with the FDA and the Australian regulator, the Therapeutic Goods Administration (TGA). The FDA is the licensing agency, but it states openly that its role is licensing drugs and not protecting the public. The TGA appears to follow the FDA in licensing drugs on the basis of company summaries. Politicians make choices that disregard those of professionals competent to make economic and safety decisions.

Congressional hearings in the United States have revealed the disparity between the knowledge held by PhaRMAs and the information, which they disclose in their advertising. New York’s Attorney General, Eliot Spitzer, won a settlement of $US430 million against Warner Lambert, a subsidiary of Pfizer Inc. for illegal and deceptive promotions of one of its blockbuster drugs, Neurontin. A score of US State attorneys have followed suit, expecting windfall income for State coffers to recoup some of the healthcare costs generated by the indiscriminate use of these drugs. “It is critically important that physicians and their patients receive fair, balanced and accurate information about prescription drugs and the conditions these medications are approved to treat,” Spitzer said. “Marketing strategies that deceptively and illegally promote drugs for unapproved purposes in order to increase a pharmaceutical company's bottom line will be aggressively investigated.”[iii]

Spitzer also conducted successful litigation against GlaxoSmithKline for non-disclosure of risk, specifically in the case of Aropax. It has obtained an undertaking by PhaRMAs to place details of clinical trials, even those previously undisclosed, on the internet. These postings on the FDA website have forensic utility to show the extent to which the advertising differs from what was found in clinical trials presented for licensing purposes.[iv]

THE PROBLEM

Completed suicide is the measurable tip of these poorly recognised psychotropic side effects, which have been systematically and deliberately discounted as “the patients’ problems.” PhaRMAs lose no opportunity to belittle David Healy, who was able through court orders to prise clinical trial statistics out of the FDA, and Peter Breggin, who was the first to bring to public notice the risks of new antidepressants and other medicines used for psychiatric purposes. Breggin defined a stimulant continuum beginning with lesser degrees of insomnia, nervousness, anxiety, hyperactivity and irritability, which progresses toward more severe agitation, restlessness, aggression and varying degrees of mania. Mania or manic-like symptoms include disinhibition, grandiosity; sleep disturbances and out-of-control aggressive behaviour. They cycle into depression and suicidality. They can produce a combined state of stimulation and depression, an agitated depression, with a high risk of suicide and violence. Panic and anxiety are common.

Obsessive preoccupations with aggression, against self or others, are often accompanied by a worsening of any pre-existing depression. Depression and suicidality may appear in persons treated for anxiety or other disorders. A state similar to personality disorder with borderline traits may appear in mature formerly stable persons. Its extreme results from a combination with alcohol and substance abuse, in what seems to be an attempt to relieve the "living hell” that the worst and most dangerous side effect, akathisia, creates. Akathisia may present as a diffuse psychomotor restlessness, which affects the patient’s entire body, an increased tenseness, insomnia and a feeling of being very uncomfortable, frequently verbalised, as "I don’t feel like myself, weird, strange, not me." Patients feel they are going mad, in turmoil, and numb as if nothing matters. Embarrassed, they do not confess their impulses. Eliciting them needs careful questioning. These experiences can go on for hours or years, or can be acted on very quickly, in a matter of minutes. Acute akathisia is a psychiatric emergency. Recurrent episodes of hallucinatory delirium along violent or sexual themes with colourful visual, voice and tactile hallucinations may be misdiagnosed as a schizophrenic illness. Sexual craving has been reported.

Akathisia has a strong association with violence, self-harm, suicide and homicide.[v] It is an inner restlessness or jitteriness, accompanied by a subjective as well as objective compulsion to move, abscond, pace or run, or drive long distances in a somewhat dissociated state. Akathisia can lead to suicide because it is intolerable. Preoccupation with unwelcome, obsessively violent thoughts is pathognomonic. First recognised in users of reserpine for high blood pressure, it became prominent in the forensic literature of the 1970s and 1980s as an effect of haloperidol and, later, of flupenthixol.[vi]

The above syndromes often appear in combination with each other. They may recede within days of stopping the medication or persist, requiring hospitalisation and additional treatment over subsequent weeks or months. They occur in individuals with no prior history of violence, suicidality, psychomotor agitation or manic-like symptoms. Some patients cannot easily stop taking these medicines without going into a state of withdrawal. They are, technically, addicted.

No single word describes the problem, but I propose “neurotoxicity spectrum disorder” to describe the manifestations of intoxication with medications said to have serotonergic and/or dopaminergic properties. Professor Perminder Sachdev has proposed a classification of one of these, akathisia. Other than in rare neurological disorders or in the aftermath of epidemics of encephalitis lethargica, akathisia is drug induced, and always iatrogenic.[vii] Acute akathisia may emerge after only two or three doses of an SSRI. It is called tardive akathisia when it develops late in treatment. Withdrawal akathisia is clinically identical and may develop up to three months after stopping the medication. It may be associated with a manic shift as well as rebound depression.  It does not get better unless akathisia inducing medications are ceased, and even then, it might take time to recede.

All phases cause serious distress, may compromise the psychiatric status of the patient, may lead to impulsive actions including aggression or self-harm, and may become chronic  and resistant to treatment. Reports ascribe to it cases of homicide and suicide. Robert Whittaker wrote about “the madman of our nightmares” who was not a schizophrenic but an akathisiac, having just taken, or taken himself off, prescribed medication.[viii] When treaters do not recognise akathisia as a toxic state and mistake it for schizophrenia, they may prescribe more neurotoxic medications that make it worse. Interactions between drugs from different manufacturers are currently nobody’s responsibility, and this complicates litigation.

Since 1994, SSRI-induced akathisia has been recognised in the Diagnostic and Statistical Manual (DSM IV TR), where it is coded as a movement disorder, but it fits equally well into drug induced psychotic states or with organic brain syndromes. A useful concept is the “akathisia-prone patient” as one who is likely to develop akathisia on tricyclics, lithium, SSRIs, Zyprexa, Risperdal, Solian and Seroquel as well as a variety of other medications. Akathisia accompanies the taking of the medication but it can also occur if the drug is stopped suddenly rather than slowly.

It should not surprise anyone to find that psychotropic drugs have psychiatric side effects, but they are poorly recognised as such, even by psychiatrists, because they occur in the context of treatment for “psychiatric” conditions. Sublethal side effects place heavy demands on Mental Health resources. It is rare to see a person who has been on these medicines for some time who is not also taking co-prescribed tranquillisers of one kind or another.

THE EVIDENCE FOR ANTIDEPRESSANT SUICIDE

Antidepressants form two major groupings, the newer ones described above, and the older ones, tri- and tetracyclics, (TCAs). The latter include Tryptanol (amitriptyline), Anafranil (clomipramine), Tofranil (imipramine), Prothiaden (dothiepin) and Sinequan (doxepin). They have their major effect on a synaptic transmitter, noradrenaline. Mood brighteners and a social phenomenon, these so-called ‘antidepressants’ act in a variety of ways to increase the levels of serotonin, most of which is in the gut, and not in the brain at all. Despite their name, there is no reliable scientific evidence that serotonin is abnormal in depression, or that SSRIs are, in any way, “specific.” Having more serotonin and different neurotransmitters floating around makes for a lot of change, not always for the best.

The possibility that a remedy could have the effect it was supposed to cure was once unthinkable, especially by clinicians, but the history of medicine is full of this type of problem. The alarm was first raised in 1990 by Harvard psychiatrist Martin Teicher. He reported six patients who after 2-7 weeks on Prozac developed intense, violent suicidal preoccupation, which persisted for 3 days to 3 months after the medication was stopped.[ix] None had experienced a similar state in the past. Drug companies dismissed such reports as “anecdotal” and gave, in effect, the reassurance that “It’s the disease, not the drug, doctor.” Pfizer's Zoloft Litigation Manual is an exhibit from Christopher Pittman’s double murder trial, provided to defend their drug in the prosecution for a bizarre Zoloft-induced homicide by a 12-year-old child.[x] There are now scores of reports of these serious adverse events in patients treated by SSRIs for anxiety, eating disorders, obsessive-compulsive disorder and menstrual problems. Most of these drugs have been banned for children in the UK and USA.

The US Supreme Court decision in Daubert v. Merrell Dow Pharmaceuticals (1993) laid the ground for a pre-trial procedure, a Daubert Hearing, by which an expert’s testimony could be examined to see if it is “scientific” and admissible, or not, to a trial.[xi] The scientific status for a theory depends on its ability to be refuted and falsified. Scientific method involves proposing a null hypothesis, and trying to demonstrate that it is false. “The unicorn does not exist” stands until a unicorn is sighted. Disproving the negative is what differentiates science from other forms of inquiry. That SSRIs induce suicide has passed six Daubert Hearings. They conclude that the science behind the revelation of induced suicide, and the problems that lead up to it, is sound.

The (dis)proof of their innocence invokes two numbers: relative risk (RR) and the suicide rate/100,000 patients, or sometimes, patient years (PEYs). Where numbers allow, they are supported by the confidence interval. A relative risk, RR, is how many more times suicide and its precursors, thinking of suicide and suicidal attempts, occur in SSRI-treated patients over and above those treated with tricyclic or sugar pills, or in similar patients in the community who are not treated at all

If a medicine saves some depressed patients from committing suicide, the RR between that medicine and no treatment should be less than one. Tricyclics generally have an RR of 0.5 against no treatment for biological depression, where suicide is a known risk. TCAs halved the number of suicides in this small and well-targeted population, which was at high risk without treatment. TCAs could also induce suicide by energising the depressed, and there is evidence that they are similar to SSRIs in this regard, but the RR was still favourable because careful management could eliminate it. SSRIs are not as effective for the biologically depressed population as are the TCAs. Clinicians will tell you we give as much electroconvulsive therapy as we ever did.

If the relative risk equals 1.0, the risk in treated individuals is the same as the risk in untreated ones. If the relative risk is more than 1.0, the risk in the treated is greater than in the untreated. As the objective is to prevent suicide, an RR of one is ominous. Eli Lilly (Prozac), Pfizer (Zoloft) and GlaxoSmithKline (Aropax) proposed in 1999 that the cut-off point of significance become an RR of 2.0, which is ridiculously high by any standard. David Healy calls this "corporate chutzpah.”[xii] At law, the exposure to asbestos is deemed contributory to cancer even though the RR is around 1.2. Asbestos was never expected to prevent cancer.

The evidence for suicide induction can be found in clinical psychiatry; in observations of new suicidal ideation and in the epidemiology of suicide by prescribed drugs; in challenge-de-challenge-re-challenge studies where suicidality starts on the drug, clears up when it is stopped and reappears on re-exposure, even to another SSRI. This is as good a proof of causality as one can get. The evidence from all these sources, population studies, primary care studies, healthy volunteer studies and random control trials overwhelmingly supports a relative risk of suicide by SSRI users of greater than 2, and sometimes, in the community, as high as 8 or 10. In a company-funded trial, the reporting of which the drug company tried to suppress, two of 26 depressed patients overdosed in the first 2 weeks when Prozac was increased quickly.[xiii] Other investigators found suicidal thinking developed in patients who had never been suicidal before, more on Prozac than on other drugs, with Prozac v TCAs having a RR of 2.7.

In 1995, against concerns that Britain’s most popular TCA, Prothiaden, was dangerously toxic in overdose and labelled as a “dirty drug” by SSRI manufacturers, Jick et al., epidemiologists, examined 172,598 persons and 1.2 million scripts for 10 antidepressants, old and new, prescribed to general practice patients of whom 143 had committed suicide.[xiv] Prothiaden turned out to be the safest, as only 14% of suicides involved antidepressant overdose. They found a suicide rate on Prozac of 274/100,000 PEYs in the first 30 days of use. This translated to 93/100,000 patients treated. The RR of suicide for Prozac v all TCAs was 6.6, the Prozac v Tofranil RR was 1.9 and the Prozac v Amitriptyline RR was 4.0.

 

Table 1: Suicides on Antidepressants in Primary Care in the United Kingdom.[xv]

Drug	Suicide Rate/ 100,000 Patients	Absolute Suicide Numbers
dothiepin lofepramine amitriptyline clomipramine imipramine doxepin flupenthixol trazodone mianserin fluoxetine	70 (C.I. 53 – 91)  26 (C.I. 8 – 61)  60 (C.I. 41 – 84)  80 (C.I. 38 – 144)  47 (C.I. 20 – 90)  69 (C.I 17 – 180)  78 (C.I. 43 – 129)  99 (C.I. 31 – 230) 166 (C.I. 86 – 285)  93	52 Suicides in 74,340 Pts  4 Suicides in 15,177 Pts 29 Suicides in 48,580 Pts  9 Suicides in 11,239 Pts  7 Suicides in 15,009 Pts  3 Suicides in 4,329 Pts 13 Suicides in 16,599 Pts  4 Suicides in 4,049 Pts 11 Suicides in 6,609 Pts 11 Suicides in 11,860 Pts
Total excluding fluoxetine                            132 Suicides per 195,931 Patients                                                                          67 Suicides per 100,000 Patients

SSRIs are advertised as safe in overdose, but Efexor XR is as lethal in overdose as amitriptyline. SSRI suicides tend to be violent. The patients talk of hanging, drowning, shooting, jumping, stabbing or cutting, lying on a railway line, burning, electrocution or deliberate road accidents. The Drug Safety Research Unit in the UK surveyed medication in a community of 50,000 people, looking at completed suicides and what medicines had been prescribed for them (Table 2). It found a suicide rate on SSRIs of 219/100,000. For Prozac it was 244/100,000, for Aropax it was 269/100,000 and for Luvox it was 183/100,000.[xvi]

Table 2:

Drug	No. Patients	No. Suicides	Suicides/ 100,000 Patients
fluoxetine sertraline paroxetine fluvoxamine	12692 12734 13741 10983	31 22 37 20	244 (C.I. 168– 340) 173 (C.I. 110– 255) 269 (C.I.192 – 365) 183 (C.I. 114– 274)
Total SSRIs	50150	110	219/100,000
mirtazapine	13,554	13	96 (C.I. 53 – 158)

                       

Boardman and Healy investigated 475,000 UK citizens over 5 years, counting all the mood disorders in all the private practices and the suicide rates for these disorders. They found primary care suicide rates for all mental disorders to be in the range of 27-67/100,000.[xvii] These figures fitted in with other primary care mood disorder suicide statistics from Holland at 30/100,000 and Sweden, 0/100,000 and the UK at 30/100,000. It would appear that hormesis, protection, had favoured persons with minor mental disorders, who get some support, making them less likely to commit suicide than one might expect. The highest possible suicide rate for mood disorders in the community that is consistent with general suicide rates is 68/100,000.

In 1999, Donovan et al. examined 222 completed suicides against their medication and found that the RR of SSRIs v TCAs was two.[xviii] Donovan also studied 2,776 deliberate self-harm (DSH) cases over 24 months. In this study, Aropax, (paroxetine) (an SSRI) had a RR of 1.9 for DSH versus Tofranil (imipramine) and an RR of 4.0 versus Amitriptyline, while the RR for Prozac was 6.6 against all TCAs.[xix]

In 2001, Khan et al. looked at blind clinical trials from 1986-90, all of which had been presented to the US Food and Drug Administration to get SSRIs licensed. Of 48,277 patients who participated in the trials, 77 committed suicide.[xx] All the clinical trials for antipsychotics, SSRIs and anticonvulsants (the medicines used for psychiatric problems) involved 71,604 participants. Khan et al. uncovered a suicide rate of those involved of 718/100,000, an increase in the rate of suicide for those participating in the SSRI clinical trials of nearly 68% over the rate of suicide in the general public, which is around 11/100,000, in citizens, and around 200/1000,000 in people getting new antidepressants.[xxi] Although the risk of suicide in untreated ‘depression’ is constantly promoted by PhaRMAs, only the relatively rare state of ‘biological depression’ carries a high suicide risk. Four per cent of the SSRI drug-trial participants attempted suicide within the following year, 4000/100,000, leading to the concern that psychiatric drugs may affect metabolism beyond their cessation. Successful suicide lies in a ratio somewhere between 1:10 to 1:20 to attempted suicide. More again become intensely preoccupied with suicide.

The results of random controlled trials (RCTs) provide the justification to have the FDA license a drug. SSRIs were aimed at general practice, so biologically depressed patients and those with borderline personality disorder, all of whom carried a suicide risk, were excluded from these trials. Investigators collected “samples of convenience” that included anxious rather than depressed patients and those under stress with minor disorders. The participants have been described as “the Valium using population of the 1970s.” The comparator drugs were mostly TCAs but some were SSRIs as well, generating a fake procedure, rather like comparing a drug to itself.

Not much difference in efficacy was ever found between placebos or old and new medications using the symptom checklist for ‘major depression’ as it appears in the DSM. Valium had been co-prescribed in the Prozac trials to combat agitation, which occurred in 25%. It may have been the active substance. Many participants had not been able to tolerate even one week’s treatment, but the FDA was not fully informed of dropout rates. Healy and Whittaker re-evaluated the original studies. They published a watershed paper in September 2003, naming it “Antidepressants and Suicide: Risk–Benefit Conundrums” (see Table 3).[xxii]

Table 3:

Investigational Drug	Patient No	Suicide No	Suicide Attempt No	Suicides & Attempts as a % of Patient No
sertraline (Zoloft) Active comparator Placebo Placebo Washout	2,053 595 786	2 0 0 0	7 1 2 3	0.44% 0.17% 0.25%
paroxetine (Aropax) Active comparator Placebo Placebo Washout	2,963 1151 554	5 3 0 2	40 12 3 2	1.52% 1.30% 0.54%
nefazodone (Serzone) Active comparator Placebo	3,496 958 875	9 0 0	12 6 1	0.60% 0.63% 0.11%
mirtazapine (Avanzar) Active comparator Placebo	2,425 977 494	8 2 0	29 5 3	1.53% 0.72% 0.61%
Bupropion (Zyban) Placebo	1,942 370	3 0	---- ----
citalopram (Cipramil) Placebo	4,168 691	8 1	91 10	2.38% 1.59%
fluoxetine (Prozac) Placebo Placebo Washout	1,427 370	1 0 1	12 0 0	0.91% 0.00%
venlafaxine (Efexor) Placebo	3082 739	7 1	36 2	1.40% 0.41%
All New Drugs All SSRIs Total Placebo	21,556 13,693 4,879	43 23 2	232 186 21	1.28% 1.53% 0.47%

Whereas Khan had coded as “placebo suicides” those within 2 weeks of stopping an SSRI, Healy and Whittaker recognised these five suicides during withdrawal or washout, and many suicidal acts, as “withdrawal suicides.” Khan had counted suicides per number of patient years exposed to the drug, PEYs, whereas Healy and Whittaker counted suicides per number of patients treated. Healy and Whittaker argued that the risks of SSRIs resembled the risks of space travel, which, mile for mile was the safest form of transport available. But going up and coming down are the danger periods for both. The metaphorical landing and re-entry occurs each time a dose is forgotten, not absorbed, taken with alcohol or if a co-prescribed medicine is added or removed. So users in the community are more likely to be adversely affected than those in clinical trials, who are interviewed about side effects each week. Healy and Whitaker’s conclusion was modest: “It is no longer possible to support the null hypothesis that SSRIs do not cause suicide.” Any way you look at available information, clinical settings, emergency rooms, morgues and clinical trials, SSRIs, as a general cause of suicide, would pass the scientific standard of proof.

David Healy conducted a healthy volunteer study using his staff. Two of 20 became suicidal in a two-week period on Zoloft.[xxiii] Two, possibly three, healthy volunteers have committed suicide in clinical trials for antidepressants. Nineteen-year-old Traci Johnston killed herself in February 2004 in a trial for incontinence of Eli Lilly’s new serotonin drug, Duloxetine, aborting the trial, but the drug was licensed in September 2004, carrying a “black box” warning

THE “SECOND GENERATION”: “ATYPICAL” ANTIPSYCHOTICS.

More alarming information has emerged from David Healy's evaluation of the clinical trials presented to the FDA of new “atypical” antipsychotic drugs.[xxiv] Because of their high cost ($300+ a month as opposed to $10 a month for haloperidol) they are limited to use for the Special Purpose (SP) of schizophrenia. In practice, they are very frequently prescribed unlawfully for all sorts of problems, with the best of intentions. They are problematic drugs. In the late 1980s, the FDA did not notice that one in 208 or 12 in 2,500 clinical trial subjects with schizophrenia committed suicide during the trials of Zyprexa, but only one on placebo and one on a comparator, most likely haloperidol. The subject numbers were so small that relative risk of suicide on Zyprexa could not be calculated reliably. The overall suicide rate for these trials, on a time-adjusted basis, was two to five times the norm for schizophrenics.

Table 4: Antipsychotic Drugs FDA Trials source FDA, David Healy[xxv]

The FDA trials and 52 subsequent studies evaluated in 2000, by John Geddes of Oxford University demonstrated no clear evidence that atypical antipsychotics were more effective or better tolerated than conventional antipsychotics.[xxvi] Thirty-six, that being one in every 145 clinical trial subjects for Risperdal, Zyprexa, Seroquel, (quietapine) and Sertindole died; most by suicide, yet these deaths are never mentioned in scientific literature or prescriber information. These deaths occurred even though two thirds of Zyprexa, nearly half the Risperdal and 80% of Seroquel subjects did not complete the trials because the drugs were poorly tolerated.[xxvii] A rate of 27% akathisia in a trial of Zyprexa 10 mg was balanced by an equally high incidence of akathisia on placebo.[xxviii] This indicated that Eli Lilly either did not know what they were talking about (as akathisia is always a medication-induced phenomenon), or the participants had not fully recovered from whatever they had been taking before entry to the trial. Serious adverse events affected 84 subjects who took Risperdal.

None of this information appears in promotional material. Indeed 47 serious adverse events in 87,000 users of Zyprexa injectable included eight deaths. We are being assured that the deaths are not related to the Zyprexa but, given the number of suicides and deaths associated with the oral preparation, this seems to be improbable. The FDA issued a ‘black box’ warning about sudden death from the new antipsychotic medications, (including quietepine and ariprazole) but only for the elderly, in spite of evidence that all age groups are adversely affected. ^[xxix][xxx] Further warnings are expected to advert to the extreme dangers of mixing them with SSRIs. Nor is it the case, as suggested, that Clozaril protects against suicide when compared with Zyprexa. Zyprexa itself is suicidogenic.[xxxi] This comparison manoeuvre delays their obligation to issue full warnings for all children and adults. The PhaRMAs are stalling again as they did for antidepressants and as Merck did for Vioxx, when they suggested that a high heart attack rate on Vioxx, compared with Naproxen, occurred because the latter was protective. David Healy has pointed out that Zyprexa and Risperdal trials had the highest suicide rates in clinical trial history, but suicide risk does not feature in drug company promotional material. Geodon (ziprasidone) had the same suicide risk as SSRIs, about one in 500.

Only five Zyprexa schizophrenia trials were undertaken, but these generated 234 ghost written articles by prominent “opinion leaders” which were carefully placed in the prestigious journals, dependent for their viability on PhaRMA advertising.[xxxii] None of these publications yielded any picture at all of the risk of suicide or suicidal acts on these drugs, let alone sudden death. “Endorsement Science” had become the means of promotion. The colourful capsules appeared on the cover of Time, in The Washington Times and The New York Times. The “Dopamine Theory of Schizophrenia” was alive and well in these endorsements, although by the time they were published it had no more scientific validity than the serotonin theory of depression. John Merson calls this phenomenon “epistemic capture,” the control of knowledge by vested interests.[xxxiii]

There is as yet no literature on suicidality when SSRIs and atypicals are used in combination. I have seen a score of cases where SSRIs had been used safely until an atypical was introduced and the patient rapidly became akathisic and suicidal. Both groups of drugs induce akathisia and have many similar side effects. Many medicines are metabolised by the P450 cytochrome system, 1000 enzymes determined by 50 different genes.[xxxiv] Not every person has all the genes and all the enzymes. Genetics of the metabolism, of transporter and neuro-receptor systems, may hold the answer to the mystery of why different people respond differently to the same substances. Some cannot deal with SSRIs at all and react catastrophically to only one or two doses. Enzymes that metabolise them can be carefully "induced" by slowly increasing doses, but they are inhibited by cannabis and some medicines. One can predict that a problem will occur with combined use, but not whether it will be suicide, violence, sedation or psychosis. If too much is given, or is given too quickly, a “traffic jam” occurs and an oversupply of psychoactive metabolites recirculates and acts, unpredictably, on brain receptors.

My guess is that the sublethal effects of medicines that have been introduced in the last 12 years in Australia would account for the increase in violent psychiatric morbidity. Schizophrenia and bipolar rates have not changed for at least a hundred years. Some more neurotoxic psychosis, technically delirium, comes from the use of amphetamines and cannabis, which together with alcohol, and smoking are risk factors for akathisia.

CONSEQUENCES DOWNSTREAM?

A study of psychiatric admissions in 2001 at Yale found that 8% of patients admitted may suffer from SSRI-induced mania or psychosis.[xxxv] The proportion seems to me more like 25 to 30% from my observation of patients, not those with borderline personality disorder, who presented in a violent state with agitation, suicidal and homicidal thoughts and acts, two or three a week, to a 21-bed rural psychiatric ward where I worked. In two years, involving about 600 admissions, 200 reports were made to the Adverse Drug Reactions Advisory Committee (ADRAC), all when the side effects described above were concurrent with SSRI use, and closely associated with dose changes. This made each hospital admission, by definition, a “serious” ADE. There were also two akathisia suicides, a death from bleeding and a Prozac homicide, all cases where collateral observations made them relatively easy to attribute.

The Bulletin revealed that 400 young mental health patients would commit suicide in 2003.[xxxvi] In NSW, the suicide rate in the immediate period after discharge was 100 times the rate for the general population; for patients with depression, it increased to 500 times. Homicides by mentally disordered persons run at three a month in NSW, having nearly doubled from 20 victims in 2000-01 to 36 in 2001-02. In the 1980s, there were only half a dozen a year for forensic psychiatrists like myself to be involved in, out of the 120 or so annual homicides in New South Wales. Dr Bill Barclay reviewed the perpetrators of nine homicides committed by patients under mental health care. Chaired by the Hon Emeritus Professor Peter Baume, Tracking Tragedy charted the rising numbers of suicides of patients under mental health care.[xxxvii]

 

Table 5: Reported suicide deaths of patients in contact with mental health services, and all suicide deaths in NSW 1993-2001[xxxviii]

Year	Suicides in NSW	Suicides in mental health care	Percent of all NSW suicides
1993	676	68	10%
1994	798	72	9%
1995	747	100	13%
1996	811	136	17%
1997	946	166	18%
1998	827	143	17%
1999	846	173	20%
2000	738	156	21%
2001	775	159	21%

Table 5 reveals that, in New South Wales, the number of suicides increased by 99 between 1993 and 2001 and suicides by persons under (state) mental health care accounted for 91 of those, most of increase in numbers in NSW. A University of Western Australia research team found annual deaths from suicide among mental health patients doubled from 1980 to 1998. In WA, 45% of suicides occurred in people who had used mental health services. The majority had one short contact following a suicide attempt and had committed suicide before receiving any follow-up. Suicide rates were seven times higher in people diagnosed with “mental illness,” and the number so diagnosed was increasing as well. The rate of suicide in people with mental illness has been increasing over the period 1990-98, and the increase in that rate almost entirely explains the net increase in the total West Australian suicide rate.[xxxix]

In the Australian Capital Territory, between 1996 and 2000, inclusive, 184 citizens died by suicide from a population of 237,798. Of these 101 were categorised as “mentally ill”, a rate 11.4 times that of the population[xl] and similar to that of excessive mortality by suicide in the mentally ill in WA and NSW. In South Australia, mental health presentations to the Accident and Emergency Department of the Flinders Medical Centre requiring Mental Health Care numbered 248 in 1994/1995 (when there were two other hospitals in the region) but had risen to 1,838 in 2002/2003, and that was not counting overdoses.[xli]

In NSW, ‘separations” for suicide attempts which had occasioned hospital admissions trebled from 3,198 in 1989 to 9,586 in 2002, and some hospitals do not report these at all. From 1990 to 2002 antidepressant use had rocketed after the first SSRI, Prozac, was introduced in 1991, Prescriptions for it and the rest rose steadily Australian doctors wrote 6,664,960 prescriptions for SSRIs in 2003. Forty per cent of first prescriptions remain unfinished, because of side effects. The national suicide rate rose again when atypical antipsychotics were made available, when Risperdal was licensed for use in schizophrenia on the Pharmaceutical Benefits Scheme from 1995, and followed by Zyprexa from early1997.  Zyprexa was licensed for bipolar illness in February 2005, as well. I predict a further increase in mental health suicide numbers as doctors co-prescribe it with SSRIs, having first mistaken their “serotonergic” side effect of unstable mood and hallucinations for bipolar disorder.

While it might be expected that mentally ill individuals are at a greater risk of suicide than the population, the increasing numbers of “mentally ill” and increasing numbers of suicides among clients of mental health services year stands as testimony to the fact that psychiatry has got something wrong. Until the error is identified and fixed, and psychiatry has solved the problems internal to it, which appear to be caused by their own remedies, more money for mental health is unlikely to help the situation. For the 300 years when bloodletting was a recommended activity for physicians, the patient, energised by a steroid boost from the shock of losing blood, would feel better but die within days. The physician, happy to be doing something, and gratified by an initial seemingly favourable response, did not look at mortality statistics or ask if he had contributed to early death.

Current priorities promoted to health ministers, State and Federal, focus on ‘depression’ and its active pharmacological treatment. Since this promotion, increasing numbers of persons have been diagnosed as ‘depressed’, until 4.7 per cent of the population is on antidepressants.[xlii] The House of Commons report of April 2005 on the Influence of the Pharmaceutical Industry expressed concern about the “Defeat Depression Campaign” (1992–1997), run by the Royal College of General Practitioners and the Royal College of Psychiatrists and sponsored by the manufacturers of antidepressants (who provided approximately one-third of the funding.) It targeted doctors as well as patients, in particular to emphasise that these drugs did not cause addiction or dependence. Any definition of dependence uses as a criterion of stopping the drug eliciting untoward effects, which they do and many people are unable to stop, hence are addicted. Witnesses argued that the use of disease awareness campaigns, which in the past have involved conditions including depression, anxiety and obesity, play a major part in the “medicalisation” of our society; in short: “where disease awareness campaigns end and disease mongering begin is a very indistinct line.”[xliii].

THE RESPONSES

PhaRMAs have settled many claims in homicide, suicide and attempted suicide lawsuits, but not enough of them to induce them to give appropriate warnings to users and prescribers in Australia.[xliv] Over 100 homicides have been defended in various jurisdictions as caused by SSRIs, their perpetrators distinguished by characteristics which make them unlikely candidates for such behaviours. Homicide is followed by suicide in an unusually high proportion of them. Involuntary intoxication leading to dissociation and automatism is raised in the defence of those who offend in this condition.[xlv] Transient global amnesia is common. The British Medical Journal issued warnings on February 5 2004, the FDA on March 22, 2004: [xlvi]

Today the Food and Drug Administration (FDA) asked manufacturers of the following antidepressant drugs to include in their labeling a warning statement that recommends close observation of adult and pediatric patients treated with these agents for worsening depression or the emergence of suicidality. It advises that anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia (severe restlessness), hypomania, and mania have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric.

Health care providers should carefully monitor patients receiving antidepressants for possible worsening of depression or suicidality, especially at the beginning of therapy or when the dose either increases or decreases.

Manufacturers in the USA put this information on web sites on May 3, 2004, but they have not amended Australian prescriber information. More than a year later, the TGA has steadfastly refuses to pass on warnings and FDA Public Health Advisories that are available to US citizens, keeping Australian prescribers and consumers in the dark. While SSRI prescribing has fallen overseas along with the share price of the makers, the TGA has posted warnings only about their use in children, in the face of evidence that the problem does not stop on the eighteenth birthday, or on the thirtieth. Marcia Angell MD, former Editor of The New England Journal of Medicine wrote, “Lets face it. The FDA is doing a poor job of ensuring that prescription drugs are safe and effective. It approves drugs that offer only minimal benefit, and then sometimes leaves them on the market long after they've been shown to be dangerous.”[xlvii]  The FDA is described as "prone to a culture of secrecy and concealment." The FDA had waived financial disclosure requirements for advisory panel members and excluded any independent authorities in psychopharmacology who have analysed the data and raised the issue of unreported suicides. Ten out of 32 panellists on the FDA had conflicts of interest in that they received income from drug companies as well.

 

On receipt of the US FDA Advisory, a spokesman for The Royal Australian and New Zealand College of Psychiatrists (RANZCP) issued a media statement saying he was "not convinced.”[xlviii] The RANZCP adopted the position of the American College of Neuropsychopharmacologists task force on SSRIs and suicide. The New York Times called these prominent opinion leaders of American psychiatry a group of “data deprived academic researchers” who “[e]ven so issued a report disputing evidence that [antidepressants] increased suicidal tendencies, only to have the FDA, which had access to all the relevant data, find that the risk was real for some depressed youngsters.[xlix][l] The RANZCP has not yet looked at suicide in adults. Sharav reported on 3/3/05, on the website of the Alliance for the Protection of Human Research, ahrp.org, that the American psychiatric establishment continued to operate within a “head in the sand” culture of denial when confronted with compelling evidence showing that their prescribing of antidepressants for children has been misguided.

Both FDA and the TCA have relied on dubious advice, incomplete drug company summaries, and false reassurances about the safety and efficacy of these drugs. The peer reviewed journal reports were based on partial (positive) data, and are, therefore, tainted. Some decisions about purchasing these substances were made under political pressure. Resistance to accepting reality and the failure to use other, non-drug, therapies may put psychiatrists at risk of malpractice suits.[li]

Doctors are expected to practice evidence-based medicine but they were never taught to differentiate ‘evidence’ from opinion, endorsement or drug company information. Evidence of the dangers of SSRIs is published and available, but requires evaluation by persons or organizations capable of assessing the evidentiary value of a report or meta-analysis. One can no longer set up another clinical trial to see how many people kill themselves as a consequence of using the drug under testing. It would be impossible to get insurance, ethics approval or informed consent. A participant would have to know that she has a 1 in 500 chance of committing suicide, a one in 70 chance of becoming suicidal, and a 20% risk of a serious adverse effect, and that she runs a significant risk of becoming violent and a small, unquantifiable risk of killing someone. Yet such trials are being proposed for elderly people dying of cancer, to see if Zoloft protects them from getting depressed. With cancer they are likely to develop liver problems and to get co-prescribed medications as well.

Potentially fatal complications of any treatment might be acceptable when the treated population is small, dangerously ill and at high risk. The availability of a supposedly safe ‘remedy’ has increased by a thousandfold the population that can be medicalised and medicated. Lethal side effects have increased by the same multiplier. It was only after the diagnosis of “depression” was expanded to include anxiety, stress, grief and unhappiness that a huge market for ‘antidepressants’ emerged.

A side effect, even suicide, when it has a rate of 1 in 500, is too rare for clinicians to see. They need advice from suicide epidemiologists and statisticians: 200/100,000 is the equivalent of one death in 500 people treated with SSRIs. If every single suicide had a “minor mental disorder,” the worst figure for suicide in untreated patients with minor disorders in the community is 67/100,000 but is more like 30/100,000 as not everyone who commits suicide has a disorder. An average figure for suicides on SSRIs is 200/100,000. This means that there are more than 100 suicides per 100,000 patients treated with serotonin boosters over treatment with other drugs or non-treatment. Sachdev writes that failing to warn of such profound side effects may attract charges of negligence and failure to get informed consent. One in 500 is well above the risk rate in the precedent set by the High Court in Rogers v Whittaker, where it was deemed that a 1 in 14,000 risk demanded a duty to warn of a catastrophic side effect. Someone should have that duty.

The manufacturers have not advised prescribers in Australia. Eli Lilly and Forrest for fluoxetine, marketed as Prozac and Lovan, and Wyeth for Efexor belatedly sent me misspelt faxes, similar in content to the US FDA Public Health Advisories. Not one of my psychiatrist colleagues recalls receiving one of these, but at the suggestion of Professor Duncan Topliss, Chair of ADRAC, prescribing information in manuals has been very quietly upgraded. (Personal communication). The risk as described in advertising remains incomprehensible to most doctors.

FUTURE ACTION

The lack of clear lines of bureaucratic responsibility and liability for medication side effects and the haphazard nature of data collection by State and Commonwealth agencies are some of the reasons why this epidemic has escaped attention from the various public health regulators. By 2003, over 28 million people had started taking Prozac since its launch in 1988. SSRIs cost the Australian taxpayer some $169 million a year for medication alone, and more has been paid out for treating the problems they have created down the line in morbidity and mortality. Had some of the cost of these drugs gone towards evaluating adverse information as it emerged in medical journals, perhaps hundreds of lives and many hundreds of millions of dollars would have been saved in health care costs.

Since 2003, the FDA has been found repeatedly, along with the National Institute of Health (NIH), to be both incompetent and corrupt.[lii] In view of this lack of reliability, legislative change is needed to ensure that the TGA protects the public interest and is competent scientifically to assess the primary evidence of clinical trials, as opposed to the PhaRMA’s spin on  them. The charter and responsibilities of the TGA needs to be reviewed to turn it into a different kind of organization, one that is accountable and responsible for the safety of drugs and provides some input into how they are used. It needs to protect the Australian consumers. These responsibilities demand that it be completely independent of the FDA and of political influences that protect the pharmaceutical industry both in Australia and in the United States. Coroners need resources to examine and collate their existing databases. The collection of data should include psychiatric post mortems on a sample of mental health suicides, together with a survey of a sample of patients presenting for psychiatric care at a number of locations.

The Melbourne Age reported on a Victorian psychiatric unit that suffered 13 suicides in 13 months, in 2002-3.[liii] It has not attracted a coronial inquiry. All the statistics available about relative risk of suicide on these drugs, the rising suicide numbers and rates correlating with increased prescribing, and the increasing number of people requiring psychiatric treatment for their side effects warrant careful public examination. Litigation arising out of these hazards against health departments and doctors could produce another medical indemnity crisis. The problem can be diverted to the source, the PhaRMAs, which collectively have deceived the Commonwealth, taxpayers, patients and prescribers. Not only the companies, but their chief executives and boards, should be held responsible for ensuring the reliability of prescribing information and be held liable for the consequences of having provided prescribers and patients with information which is false or misleading, misrepresented or intentionally withheld.

The Author: Dr Yolande Lucire PhD MBBS DPM FRANZCP is a forensic psychiatrist and medical anthropologist in private practice. She researches and writes about hysteria and moral panics, and is surprised to find a panic worth having that is hard to start. Correspondence to lucire@ozemail.com.au

The Occasion: Plenary session of the New South Wales Chapter of the Academy held on 19th May, 20004 to discuss if second generation antidepressants and SSRIs induced suicide.