Hostility Events in Adult and Paediatric Placebo-Controlled Trials on Therapy and in Withdrawal Phase

In these trials, hostile events are found to excess in both adults and children on paroxetine compared with placebo, and are found across indications, and both on therapy and during withdrawal. The rates were highest in children with obsessive-compulsive disorder (OCD), where the odds ratio of a hostile event was 17 times greater (95% confidence interval [CI], 2.22–130.0).

In their submissions to the Committee on Safety of Medicines Expert Working Group, GlaxoSmithKline also reported that 11,491 patients entered trials comparing paroxetine with other antidepressants [5]. In this patient cohort, 44 hostile events occurred on paroxetine or other drugs, a rate of 0.38%. In the subset of trials comparing paroxetine with another SSRI, there were 16 hostile events in 2,418 patients (0.66%). These SSRI comparator trials may be confounded by indication; the SSRI comparator trials might, for instance, have included a higher proportion of patients with OCD.

Finally, in healthy volunteer studies, hostile events occurred in three of 271 (1.1%) volunteers taking paroxetine, compared with zero in 138 taking placebo [5]. Although not statistically significant, this finding is striking because hostile events are unusual in healthy volunteer trials, and this figure was higher than the rate reported in clinical populations above. GlaxoSmithKline ascribed these episodes to the fact that the volunteers were confined, although this applied to both paroxetine and placebo volunteers. One other healthy volunteer study has reported aggressive behaviour in one volunteer taking sertraline [8].

In data from sertraline paediatric trials submitted by Pfizer, aggression was the joint commonest cause for discontinuation from the two sertraline placebo-controlled trials in depressed children [9]. In these trials, eight of 189 patients randomised to sertraline discontinued for aggression, agitation, or hyperkinesis (a coding term for akathisia), compared with no dropouts for these reasons in 184 patients on placebo (95% CI, 1.72–infinity). When discontinuations for any manifestation of treatment-induced activation (suicidal ideation or attempts, aggression, agitation, hyperkinesis, or aggravated depression) were considered, there were 15 discontinuations on sertraline compared with two on placebo, a relative risk of 7.3 (95% CI, 1.70–31.5; p = 0.0015). The report of these studies does not include an analysis of these data [9]. In the only other placebo-controlled sertraline paediatric trial, undertaken in children and adolescents with OCD, there were ten dropouts out of 92 patients on sertraline, five of whom discontinued for behavioural activation, two for agitation, one for aggression, one for nervousness, and one for emotional lability. In comparison, there was one discontinuation for hyperkinesis out of a total of two dropouts from 95 patients on placebo [10].

Finally, in paediatric trials of venlafaxine (Wyeth), two percent of children dropped out because of hostility, more than double the rate of dropout on placebo [11].

By 2003, 121 cases of aggression on paroxetine had been reported to the Medicines and Healthcare Products Regulatory Agency (MHRA), and by January 2006 that number had risen to 211 [12]. It should be noted that such reporting systems estimate that physicians report between one and ten percent of adverse effects on treatment [13].

Antidepressants and Violence

Recent regulatory warnings about adverse behavioural effects of antidepressants in susceptible individuals have raised the profile of these issues with clinicians, patients, and the public. We review available clinical trial data on paroxetine and sertraline and pharmacovigilance studies of paroxetine and fluoxetine, and outline a series of medico-legal cases involving antidepressants and violence.

Both clinical trial and pharmacovigilance data point to possible links between these drugs and violent behaviours. The legal cases outlined returned a variety of verdicts that may in part have stemmed from different judicial processes. Many jurisdictions appear not to have considered the possibility that a prescription drug may induce violence.

The association of antidepressant treatment with aggression and violence reported here calls for more clinical trial and epidemiological data to be made available and for good clinical descriptions of the adverse outcomes of treatment. Legal systems are likely to continue to be faced with cases of violence associated with the use of psychotropic drugs, and it may fall to the courts to demand access to currently unavailable data. The problem is international and calls for an international response.

In 1989, Joseph Wesbecker shot dead eight people and injured 12 others before killing himself at his place of work in Kentucky. Wesbecker had been taking the selective serotonin reuptake inhibitor (SSRI) antidepressant fluoxetine for four weeks before these homicides, and this led to a legal action against the makers of fluoxetine, Eli Lilly [1]. The case was tried and settled in 1994, and as part of the settlement a number of pharmaceutical company documents about drug-induced activation were released into the public domain. Subsequent legal cases, some of which are outlined below, have further raised the possibility of a link between antidepressant use and violence.

The issue of treatment-related activation has since then been considered primarily in terms of possible increases in the risk of suicide among a subgroup of patients who react adversely to treatment. This possibility has led regulatory authorities to warn doctors about the risk of suicide in the early stages of treatment, at times of changing dosage, and during the withdrawal phase of treatment. Some regulators, such as the Canadian regulators, have also referred to risks of treatment-induced activation leading to both self-harm and harm to others [2]. The United States labels for all antidepressants as of August 2004 note that “anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor 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” [3]. Despite these developments, few data are available on the links between antidepressant usage and violence. We here offer new data, review the implications of these data, and summarise a series of medico-legal cases.

This paper focuses on paroxetine primarily because we have access to more illustrative medico-legal case material for this drug than for other antidepressants. Secondly, the manufacturer, GlaxoSmithKline, submitted data on the rates of occurrence of “hostile” episodes on paroxetine for the recent review of antidepressant drugs undertaken by the British regulator [4,5]. It is not clear that the review team obtained comparable data for other antidepressants.

Serotonin and Depression

In 1965, Joseph Schildkraut put forth the hypothesis that depression was associated with low levels of norepinephrine [6], and later researchers theorized that serotonin was the neurotransmitter of interest [7]. In subsequent years, there were numerous attempts to identify reproducible neurochemical alterations in the nervous systems of patients diagnosed with depression. For instance, researchers compared levels of serotonin metabolites in the cerebrospinal fluid of clinically depressed suicidal patients to controls, but the primary literature is mixed and plagued with methodological difficulties such as very small sample sizes and uncontrolled confounding variables. In a recent review of these studies, the chairman of the German Medical Board and colleagues stated, “Reported associations of subgroups of suicidal behavior (e.g. violent suicide attempts) with low CSF–5HIAA [serotonin] concentrations are likely to represent somewhat premature translations of findings from studies that have flaws in methodology” [8]. Attempts were also made to induce depression by depleting serotonin levels, but these experiments reaped no consistent results [9]. Likewise, researchers found that huge increases in brain serotonin, arrived at by administering high-dose L-tryptophan, were ineffective at relieving depression [10].
Contemporary neuroscience research has failed to confirm any serotonergic lesion in any mental disorder, and has in fact provided significant counterevidence to the explanation of a simple neurotransmitter deficiency. Modern neuroscience has instead shown that the brain is vastly complex and poorly understood [11]. While neuroscience is a rapidly advancing field, to propose that researchers can objectively identify a “chemical imbalance” at the molecular level is not compatible with the extant science. In fact, there is no scientifically established ideal “chemical balance” of serotonin, let alone an identifiable pathological imbalance. To equate the impressive recent achievements of neuroscience with support for the serotonin hypothesis is a mistake.

With direct proof of serotonin deficiency in any mental disorder lacking, the claimed efficacy of SSRIs is often cited as indirect support for the serotonin hypothesis. Yet, this ex juvantibus line of reasoning (i.e., reasoning “backwards” to make assumptions about disease causation based on the response of the disease to a treatment) is logically problematic—the fact that aspirin cures headaches does not prove that headaches are due to low levels of aspirin in the brain. Serotonin researchers from the US National Institute of Mental Health Laboratory of Clinical Science clearly state, “[T]he demonstrated efficacy of selective serotonin reuptake inhibitors…cannot be used as primary evidence for serotonergic dysfunction in the pathophysiology of these disorders” [12].
Reasoning backwards, from SSRI efficacy to presumed serotonin deficiency, is thus highly contested. The validity of this reasoning becomes even more unlikely when one considers recent studies that even call into question the very efficacy of the SSRIs. Irving Kirsch and colleagues, using the Freedom of Information Act, gained access to all clinical trials of antidepressants submitted to the Food and Drug Administration (FDA) by the pharmaceutical companies for medication approval. When the published and unpublished trials were pooled, the placebo duplicated about 80% of the antidepressant response [13]; 57% of these pharmaceutical company–funded trials failed to show a statistically significant difference between antidepressant and inert placebo [14]. A recent Cochrane review suggests that these results are inflated as compared to trials that use an active placebo [15]. This modest efficacy and extremely high rate of placebo response are not seen in the treatment of well-studied imbalances such as insulin deficiency, and casts doubt on the serotonin hypothesis.

Also problematic for the serotonin hypothesis is the growing body of research comparing SSRIs to interventions that do not target serotonin specifically. For instance, a Cochrane systematic review found no major difference in efficacy between SSRIs and tricyclic antidepressants [16]. In addition, in randomized controlled trials, buproprion [17] and reboxetine [18] were just as effective as the SSRIs in the treatment of depression, yet neither affects serotonin to any significant degree. St. John's Wort [19] and placebo [20] have outperformed SSRIs in recent randomized controlled trials. Exercise was found to be as effective as the SSRI sertraline in a randomized controlled trial [21]. The research and development activities of pharmaceutical companies also illustrate a diminishing role for serotonergic intervention—Eli Lilly, the company that produced fluoxetine (Prozac), recently released duloxetine, an antidepressant designed to impact norepinephrine as well as serotonin. The evidence presented above thus seems incompatible with a specific serotonergic lesion in depression.

Although SSRIs are considered “antidepressants,” they are FDA-approved treatments for eight separate psychiatric diagnoses, ranging from social anxiety disorder to obsessive-compulsive disorder to premenstrual dysphoric disorder. Some consumer advertisements (such as the Zoloft and Paxil Web sites) promote the serotonin hypothesis, not just for depression, but also for some of these other diagnostic categories [22,23]. Thus, for the serotonin hypothesis to be correct as currently presented, serotonin regulation would need to be the cause (and remedy) of each of these disorders [24]. This is improbable, and no one has yet proposed a cogent theory explaining how a singular putative neurochemical abnormality could result in so many wildly differing behavioral manifestations.

In short, there exists no rigorous corroboration of the serotonin theory, and a significant body of contradictory evidence. Far from being a radical line of thought, doubts about the serotonin hypothesis are well acknowledged by many researchers, including frank statements from prominent psychiatrists, some of whom are even enthusiastic proponents of SSRI medications (see Table 1).

However, in addition to what these authors say about serotonin, it is also important to look at what is not said in the scientific literature. To our knowledge, there is not a single peer-reviewed article that can be accurately cited to directly support claims of serotonin deficiency in any mental disorder, while there are many articles that present counterevidence. Furthermore, the Diagnostic and Statistical Manual of Mental Disorders (DSM), which is published by the American Psychiatric Association and contains the definitions of all psychiatric diagnoses, does not list serotonin as a cause of any mental disorder. The American Psychiatric Press Textbook of Clinical Psychiatry addresses serotonin deficiency as an unconfirmed hypothesis, stating, “Additional experience has not confirmed the monoamine depletion hypothesis” [25].

Percent of Fluoxetine Dispensed for Depression

By examining the data on fluoxetine dispensation for the specific associated disorders, we found, as expected, that for the period 2002–2004, depression was the primary reason that these drugs were dispensed. Using this sample time period, as an indicator of relative use of these drugs, we found that for the period 2002–2004, major depression was the reason for 72.1% of all fluoxetine that was dispensed, with the other 27.9% dispensed for the following disorders in order of frequency: anxiety (6.2%), obsessive-compulsive disorder (5.7%), schizophrenia (2.2%), stress (2.0%), premenstrual syndrome (1.0%), phobias (0.8%), eating disorders (1.0%), and all others unclassified (8.8%).

Fluoxetine Prescription Data

We obtained the estimates for the prescription trends and dispensed numbers for fluoxetine from IMS Health USA, the leading international provider of data on drug use to the pharmaceutical and healthcare industries. The data for fluoxetine were extracted from their extensive National Prescription Audit database in Philadelphia, which provides information based on dispensed prescriptions from retail, mail service, and LTC pharmacies. National Prescription Audit data are projected to a national level from a sample of over 20,000 retail pharmacies. These data are representative of the total dispensed prescriptions for fluoxetine from when it was introduced to the market in 1988–2002. The dispensed numbers were reported in thousands for the formulations Prozac (SMRY 0188 LLY), Prozac Weekly (SMRY 0301 LLY), and fluoxetine-HCl (SMRY 0000 USA). The fluoxetine-HCl generic formulation and Prozac Weekly formulation were first introduced in 2001. The numbers for the Prozac Weekly regimen were multiplied by seven in order to account for the single weekly dispensation of this type of formulation and to adjust for the dispensation numbers in correlation with rest of the daily-dispensed data.

The fluoxetine data on the percent of dispensation for specific disorders were obtained independently of the yearly dispensed data from IMS Health for the period of 2002–2004, with 2002 being the first year that they kept track of this type of information in their database. These data provided a specific list of disorders that fluoxetine was prescribed for and the relative percentage of dispensation of fluoxetine in the given year for these disorders. See Table 2 for suicide rates and fluoxetine prescription data for the period 1988–2002.

Fluoxetine Prescriptions and Suicide Rates in the United States

Depression is very common. For example, in the US, an estimated 10% of men and 20% of women will suffer from major depression at some stage in their lives. One way of treating the condition is with drugs. Several types of antidepressant drugs are available, and in many countries they are among the most commonly prescribed medicines. However, all antidepressants have side effects.

One family of antidepressants, called selective serotonin uptake inhibitors (SSRIs), was introduced in the late 1980s. The name of these drugs comes from their effect, which is to prevent the removal (reuptake) from the nerve endings of one type of chemical (serotonin) that is important for transmitting nerve impulses between brain cells. SSRIs are claimed to be more effective and to have fewer side effects than older antidepressants, and many brands of SSRI are now on the market. However, in recent years there have been claims that some people taking SSRIs have committed suicide as a result of the drugs. Whether the SSRIs are the cause of the suicide is hard to know, because people who are depressed do sometimes feel like killing themselves; so if a depressed person taking an SSRI commits suicide, it is hard to tell whether this is a result of the depression or a side effect of the treatment (the SSRI). The drug regulatory authorities in some countries are now carefully studying the issue of suicides and antidepressant use, both in adults and in children. The US Federal Drug Administration has issued what it calls a “black box warning” on the use of these drugs.

The researchers wanted to discover whether the number of suicides in the US had increased or decreased since treatment with the first widely used SSRI (fluoxetine, also known as Prozac) began in 1988. Any difference in the number of suicides found before and after that date would not necessarily be the result of the introduction of this antidepressant, or other SSRIs, but the information would provide helpful information about the effects of these drugs.

They looked at annual suicide rates between 1960 and 1988 and compared them with annual rates in the period 1988 to 2002. They used several sources of data, including the Centers of Disease Control and the US Census Bureau. The researchers found that from the early 1960s until 1988, in the entire US population, between 12.2 and 13.7 people in every 100,000 committed suicide each year. After that time, the numbers of suicides gradually declined, with the lowest figure (10.4 people per 100,000) reached in 2000. The researchers did mathematical tests, which demonstrated that the steady decline was statistically associated with the increased number of fluoxetine prescriptions—that is, the more prescriptions there were, the fewer suicides there were. (There were around two-and-a-half million prescriptions of the drug in 1988, increasing to over 33 million in 2002.)

In all scientific research, it is an important principle that finding an association between two events does not prove that one caused the other to occur. However, the authors of this paper suggest that the use of this drug could have contributed to the reduction of suicide rates in the US in the period 1988 to 2002. Several other SSRIs are also now in common use, but they were not considered in this study, nor were other antidepressants, or other treatments for depression.

As depression is such a common condition—and because there are so many ways of treating it, including counseling and psychotherapy—there are many Web sites devoted to the subject. We have given a small selection below.

Because of evidence made available in recent months, US and UK regulatory agencies have been critically examining suicidality and antidepressant use in children and adults. The crucial point is whether antidepressants increase suicidality over and above what is caused by the underlying disorders, such as major depression. With such recent scrutiny of antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs) and the US Food and Drug Administration-recommended “black box warning,” it becomes timely to examine temporal trends in suicide and to study the potential impact of antidepressants on mortality caused by self-harm.

This is a complex task because while on the one hand acute antidepressant use has been associated with suicidality, but untreated depression is also the major cause of suicide . Therefore, two competing hypothesis exist. The first is that the acute effects of antidepressants can induce suicidality, and the second is that by effectively treating depression, antidepressants can reduce the rates of suicide.

Major depressive disorder is a common and complex disorder of gene-environment interactions, for which there is no curative treatment [2–4]. The disorder afflicts approximately 10% of American men and 20% of American women over their lifetimes. The point prevalence is in the range of 3% (2% in men, 4% in women) [5,6], but increases up to 10% in the elderly [7,8]. Because the prevalence of depression is so high, and treatment lasts several months to years, antidepressant pharmacotherapy is among the most frequently used treatments in all of medical therapeutics.

Depression is itself the most prevalent cause of suicides [1], and suicide is, in turn, still among the major causes of death. According to the latest figures from the Centers for Disease Control and Prevention (CDC), in the United States in 2002, suicide was the eleventh leading cause of death (in 1998 it was the eighth leading cause of death). When the data are analyzed by age cohort, suicide is the fifth leading cause of death in the age group 5–14, the third leading cause of death in the age group 15–24, and the fourth cause of death in the age group 25–44 (Table 1) [9]. It has been estimated that 60%–70% of acutely depressed patients experience suicide ideations [10]. It is universally agreed that depression increases the risk for suicide. However, the extent of the risk has been a subject of debate. The figure of lifetime risk for suicide in patients with major depression had been commonly quoted as in the range of 10%–20% [10–12], based on the study of hospitalized patients. However, recent studies have examined other types of samples and found a much lower risk, reported as 6% by Inskip et al. [13] based on a meta-analysis, 3.4%–3.5% (7% in males and 1% in women) based on gender and age-stratified calculations made on the entire population [14,15], and 2.4% based on analysis of a community sample in England [16]. An interesting meta-analysis in which papers were stratified by type of presentation revealed that in patients hospitalized for suicidality the lifetime prevalence of suicide was 8.6%; for affective disorder patients hospitalized without specification of suicidality, the lifetime risk of suicide was 4.0%, and for mixed inpatient/outpatient populations it was 2.2%; for the nonaffectively ill population, it was less than 0.5% [17]. Depression appears to be present in at least 50% of all suicides in adults [18,19]; in children that rate has been reported to be in the range of 62%–76% [20,21].

Peds Dosing Prozac

Dosage forms: 10,20,40; 20/5 mL sol
major depressive disorder
8-17 yo
Dose: 10-20 mg PO qd; Start: 10 mg PO qd x7 days; Info: slower titration in lower wt peds; taper dose gradually to D/C
obsessive-compulsive disorder
7-17 yo
Dose: 20-60 mg PO qd; Start: 10 mg PO qd, incr. 10 mg/day q14 days; Info: slower titration, max 20-30 mg/day in lower wt peds; taper dose gradually to D/C
renal dosing
no adjustment
HD: not defined
hepatic dosing
adjust dose amount, frequency
hepatic impairment: decr. dose or frequency, amount not defined

Peds Dosing Prozac

Dosage forms: 10,20,40; 20/5 mL sol
major depressive disorder
8-17 yo
Dose: 10-20 mg PO qd; Start: 10 mg PO qd x7 days; Info: slower titration in lower wt peds; taper dose gradually to D/C
obsessive-compulsive disorder
7-17 yo
Dose: 20-60 mg PO qd; Start: 10 mg PO qd, incr. 10 mg/day q14 days; Info: slower titration, max 20-30 mg/day in lower wt peds; taper dose gradually to D/C
renal dosing
no adjustment
HD: not defined
hepatic dosing
adjust dose amount, frequency
hepatic impairment: decr. dose or frequency, amount not defined

Prozac
fluoxetine

Dosage forms: 10,20,40; 20/5 mL sol
major depressive disorder
20-60 mg PO qam
Start: 20 mg PO qam, incr. after several wk prn; Info: doses >20 mg/day may be given bid; taper dose gradually to D/C
obsessive-compulsive disorder
20-80 mg PO qam
Start: 20 mg PO qam, incr. after several wk prn; Info: doses >20 mg/day may be given bid; taper dose gradually to D/C
bulimia nervosa
60 mg PO qam
Info: titrate dose up to 60 mg over several days; taper dose gradually to D/C
panic disorder
20 mg PO qam
Start: 10 mg PO qam x7 days; Max: 60 mg/day; Info: taper dose gradually to D/C
renal dosing
no adjustment
HD/CAPD: not defined
hepatic dosing
adjust dose amount, frequency
hepatic impairment: decr. dose or frequency, amount not defined

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