CASE REPORT
Akathisia-related homicide
Lucire
Antidepressant-induced akathisia-related homicides associated with diminishing mutations in metabolizing genes of the CYP450 family
Yolande Lucire
Edgecliff Center, Edgecliff, Sydney, New South Wales, Australia
Correspondence: Dr Yolande Lucire
Level 5, 203–233 New South Head Road, Edgecliff Centre, Edgecliff, NSW 2027, Australia
Tel +2 9327 1499
Fax +2 9327 4555
Abstract
Background: As soon as genetic testing became available in Australia, it was offered to the investigator’s patients with experience of prolonged and serious adverse drug reactions to antidepressants, antipsychotics, and other brain-targeting drugs metabolized by the cytochrome P450 system (CYP450). This paper describes unmotivated homicides and serious attempts to kill, and the mental state that accompanied them, in this patient group.
Methods: Patients were tested for CYP450 activity because they had developed akathisia, with suicidal and/or homicidal thoughts, impulses, and actions while taking antidepressant medications in a study aiming to correlate these adverse drug reactions with metabolizing genes of the CYP450 family.
Results: Among 130 patients monitored to date, seven who had committed a homicide were identified, and more who had made serious attempts at homicide. CYP450 2C19*17 seemed to be overrepresented among those with the most severe reactions. Side effects were poorly recognized and were treated with drugs marketed as mood stabilizers or antipsychotics which required metabolic pathways similar toantidepressants.Slow withdrawal led to full recovery, but took a long time. Some patients developed neuroleptic brain injury.
Conclusion: People who become violently akathisic, suicidal and/or homicidal on single doses of antidepressants do not metabolize drugs normally and do not have “wild-type” extensive metabolizer genes. Similar outcomes may be achieved by overmedication and coprescribing of drugs that compete for or inhibit CYP450 metabolism. Decreased CYP450 metabolism appears to be causally linked with the most severe and violent side effects of antidepressants.
Keywords: antidepressants, akathisia, suicide, homicide, adverse drug reactions, pharmacogenomics, violence, CYP450, 2D6, 2C9, 2C19, 2C19*17.
Introduction
Most medicines used to change the brain's chemistry are metabolized by an enzymatic system known as the cytochrome P450 (CYP450) system, the activity of which is genetically determined. For the purpose of safety pharmacogenomics, the general population can be broadly divided by genetic testing into poor, intermediate, extensive (normal, “wild-type”), and ultrarapid metabolizers for one or more cytochromes1 (see Table 1). The Karolinska group, led by Sundberg, maintains a website (see summarizing the relevant literature on the metabolizing functions of different alleles.
Conditions that affect drug metabolism include: coprescribed medications that induce or inhibit the enzymatic pathways, ie, age, nutrition, stress, liver disease, and both natural and extraneous hormones; the sequence in which drugs have been prescribed or taken away; the route of administration; the range of the drug’s half-life in any population; potentially multiple metabolic pathways; the size of the therapeutic window above which a drug is both ineffective and toxic; the duration of therapy; and the duration of inhibition which may persist after discontinuation.2,3
Some extensive metabolizers metabolize drugs similarly to poor metabolizers after taking CYP450 inhibitors that reduce or eliminate enzyme activity.4,5 Some intermediate metabolizers may metabolize like extensive metabolizers but, because testing was offered only to those with serious adverse drug reactions, any possible normally metabolizing extensive metabolizers did not appear in this series.6 With some drugs and prodrugs, ultrarapid metabolism producing an active metabolite was found to be problematic, particularly during withdrawal.7
High or fast-changing levels of psychotropic substances cause unpredictably toxic and violent behavioral effects (as listed in each drug’s product information or “labeling”).8 Extrapyramidal side effects, including akathisia, develop more rapidly in persons with slower metabolism and in children whose cytochrome systems and other metabolic pathways have not yet developed or been induced.9,10
History of this study
When CYP450 testing became available, it was initially offered to patients in the author’s practice who had suffered from violent and suicidal akathisia for up to seven years. These patients had been suicidal and homicidal on antidepressants prescribed for work stress, anxiety, or bereavement, and, after developing side effects, they had been diagnosed with serious mental illness and stigmatized by their diagnoses. All had eventually returned to normality after slow withdrawal of the culprit drugs.
Early results from the Diversity Health Institute at Westmead Hospital, which tested for only the main seven alleles, were encouraging, with akathisia subjects showing significantly higher rates of mutations and more multiple mutations than the population of western Sydney (Figure 1).11 The akathisia subjects also had more mutations and more multiple mutations than a clinical population from central Melbourne which tested for 18 out of the same 19 alleles, when adjusted to the same criteria. While the populations were not strictly comparable, and may have been clinically and ethnically different, multiple mutations were many times more frequent in those with serious adverse drug reactions, with a shift to the right of the distribution curve.
Support from Healthscope Molecular in Victoria enabled testing of patients with serious adverse drug reactions (who could not pay for the tests themselves) to lay the foundation for a prospective study in which every result was coded into a FileMaker database constructed for this purpose. Workers compensation and motor accident insurers paid for these tests because they could potentially account for nonrecovering depression and failed analgesia.
The original plan was to correlate serious adverse drug reactions with three metabolizing genes of the CYP450 family and specific antidepressants. This was not possible because only 29 of the patients had been taking an antidepressant on its own at any point in their multiple episodes of treatment, and only 10 of them had taken a standard dose. Most of these patients had also used alcohol and some had used cannabis concomitantly. Nearly all had been on polypharmacy before, during, and after antidepressant therapy.
Method
More than 100 persons who had developed akathisia-related suicidal and homicidal impulses were tested for CYP450 activity. About 20 others were also tested, including three lacking an analgesic response to opioid prodrugs, two who had became aggressive on hypericum, one who had sleepwalked to her death on zolpidem and zopiclone, and the remainder of the group comprised first-degree relatives, some with their own adverse drug reactions. Patients signed informed consent for testing and inclusion in the series. Those described in this report gave their written permission for their data to be published. No ethics approval was required to document observations and test results, so none was sought.
Antidepressants, akathisia, violence, suicide, and homicide
New-generation antidepressants and atypical antipsychotics at least doubled suicide rates compared with placebo in the clinical trials presented to the US Food and Drug Administration (FDA) for licensing.12,13 Professor David Healy, who has accessed various drug company archives with court ordered approval, gave the following evidence to a House of Commons inquiry:
First, in order for a drug to be licensed, it has to show superiority to placebo in two controlled trials. Companies however can run ten or more trials in carefully selected samples using instruments carefully designed to pick up any effect in order to demonstrate this, and even if the results show the drug failing to beat placebo in the clear majority of trials, this is not held against them. These other trials are commonly termed failed trials rather than drug failures.14
When the US FDA was made aware of successful litigation based on suicide epidemiology and the bulk of evidence, and having held some public hearings, it ordered that a Black Box warning about their effects in children, part of a “class suicidality labeling language for antidepressants” be incorporated in each drug’s product information, part of which reads as follows:
WARNINGS – Clinical Worsening and Suicide Risk
Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. There has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients.
The following symptoms of 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.15
In June 2005, the FDA conceded causation of suicide by antidepressants and later extended suicide warnings to other drugs.16Australian prescribers and patients were not advised of this problem by the relevant authority, ie, the Therapeutic Goods Administration. The Therapeutic Goods Administration did not follow or adopt any of the public health advisories produced by the FDA, nor did it demand that drug companies notify prescribers of these major changes or include them in Australian prescribing information.17Failing to make clear that these effects are not related to the psychiatric diagnosis causes some Australian prescribers to believe they are seeing an exacerbation of a psychiatric condition rather than a neurotoxic side effect, ie, a toxidrome.
Adverse drug reactions can be idiosyncratic, dose-related, or both. Adverse drug reactions can be idiosyncratic, dose-related, or both. If the genes producing the relevant cytochromes are mutated or their metabolism is inhibited by other drugs, the enzyme is not functional, and the “victim” drug, the substrate, is not metabolized and not eliminated.Levels rise above the therapeutic window, and the treated condition is replaced by neuroleptic toxicity. Such “idiosyncratic” responses relate to individuals not to conditions. They are not evidence of “uncovered bipolar”, as suggested by antidepressant prescribing information, or of “schizophrenia” or “depression coming back”. They are toxidromes, the symptoms of which may resemble psychiatric, medical, or neurological conditions.18 Recovery from the condition being treated is no longer possible, because the toxidrome is experienced by the patient as violence, confusion, hallucinosis, suicidal and homicidal impulses, and a death wish.
Tricyclic and tetracyclic antidepressants were able to halve suicide rates in patients treated for major depressive disorder with biological features (Feigner criteria)19 and did so because the risk of suicide in this kind of depression is high (the denominator in relative risk calculations) and because these antidepressants were carefully prescribed, at least by psychiatrists. Occasional medication-induced suicides were known to occur, and they were a matter of textbook psychiatry in the 1960s, before they were recognized as acute akathisia.20 Increasing from a low dose could control for this risk by used to be carefully monitored in the treatment of severe depression, warning the patient that suicidal and violent impulses may occur. The giving of such a warning in Case 3, described later, might have prevented the nortriptyline-induced homicide that occurred.
Because akathisia (particularly when combined with serotonergic states) is associated with suicide, antidepressants increased the suicide risk when given to a population at low risk of suicide.21,22 In this series, no patient was being treated for biological depression, although a few may have suffered from dysthymia. Most came from a compensation stream, and were experiencing work stress, bereavements, anxiety, anorexia, low mood associated with substance abuse, alcohol abuse, and/or painful injuries.
In 2008/2009, the Therapeutic Goods Administration commissioned an expert report on 90 of the investigator's cases of akathisia and serotonin syndrome reported in 2007 alone. These cases comprised personal injury and work stress claimants seen before genetic testing was being performed. The expert advisory panel made many excellent recommendations at that time.23
Adverse drug reactions reported in the product information for antidepressants in the US include suicide attempts, completed akathisia-related suicide, aggression, homicidal ideation (in venlafaxine's Product Information: 1996-7; after that it disappeared), toxic psychosis/hallucinosis, psychic numbing, deterioration in mental state, confusion, worsening depression, thoughts of death or dying, and/or mania manifesting as violence directed towards self or others, as well as cognitive impairment.
In the US, five Daubert hearings have determined that the evidence underpinning antidepressant-induced akathisia-related suicide and homicide is scientifically sound. Daubert hearings and US science courts eliminate personal opinions and junk science, and ensure that expert evidence meets the criteria of Popperian science.24–26 Pharmacological causes of suicides, homicides, and other violent crimes are poorly recognized and are not being investigated in Australia.27
In parallel with the release of each new psychiatric akathisia-inducing drug since 1990 has come an increasing demand for mental health care with the number of persons seeking care doubling in the decade after the introduction of the first new generation antidepressant, fluoxetine in 1990. Persons treated for trivial complaints need care for unexpected side effects. In parallel with this increased demand for services there is an increased rate of suicide in patients under care and of hospitalized suicide attempts.28 The epidemic of medication-induced mental illness has been documented in USA by RobertWhitaker.29 Between January 1, 2003 and December 31, 2009, the NSW Mental Health Sentinel Events Review Committee documented steadily rising numbers of suicides and homicides committed by persons under state mental health care in New South Wales.30,31 Little is known about these statistics in private practice. Suggestions that this committee might, in cases of suicide and homicide, investigate medication, concurrent akathisia, metabolizing genes and commission psychological autopsies have not been taken up.
The relevant product information reports that all antidepressants and antipsychotics cause akathisia to varying degrees. Burgess et al found that, after psychiatric services were introduced to 100 developing countries, suicide rates rose in all of them.32 Links between neuroleptics, antidepressants, akathisia, suicide, and aggression have been included in the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, since 1994.21
Genetically impaired CYP 2D6 activity is known to increase the risk of antipsychotic-induced extrapyramidal syndromes, and prolong hospital stays, increasing costs.33 Poor metabolizers should have their doses reduced when metabolism of the prescribed drug depends on CYP2D6 activity, or should receive an antipsychotic drug that is less CYP2D6-dependent.
Drugs as diverse in structure and function as hypericum (St. John’s wort), varenicline (Chantix®), oseltamivir (Tamiflu®), isotretinoin (Roaccutane®) mefloquine (Lariam®), metoclopramide (Maxolon®), zolpidem (Stilnox®, Ambien®), calcium channel blockers, antiepileptic drugs mooted as “mood stabilizers”, reserpine, statins, and interferon, all induce suicidal and homicidal thinking as an occasional side effect.34,35 Moore et al identified 1527 cases of violence disproportionally reported to the FDA for 31 drugs, ie, varenicline, 11 antidepressants, 2 atypical antipsychotics, six sedative/hypnotics, and three drugs used for attention-deficit hyperactivity disorder.36
Akathisia has been associated with suicide since the 1950s and with homicide since 1985. Shear et al reported homicides associated with akathisia after treatment with depot fluphenazine.37Cem Atbasoglu et al examined the relationship between suicidality and depersonalization in akathisia.38Schulte described five cases of murder, suicide and severe violence with akathisia in psychiatric patients.39 Healy et al described five cases involving antidepressants, violence and homicides in patients who had not been mentally ill before being medicated.40On their website, Bostock and Gardner, well known as “pharmacovigilantes”, have documented over 4000 selective serotonin reuptake inhibitor-induced massacres, homicides, suicides, and school and college medication-related shootings dating back to 1966, along with drugs and legal defenses in some cases.41Breggin describes escalation from anxiety through to insomnia, manic symptoms of varying degrees, suicidal impulses, aggression, homicidal thoughts, experiences of body parts changing, feelings of unreality, psychic numbing, akathisia, and violence with antidepressants. Affected patients kill in a toxic delirium, while sleepwalking or in a state of dissociation with automatism, sometimes following a psychological blow.42
Experiences of some subjects
Case 1
A male patient, aged 18 years, with a 2D6*4*5, 2C91*1, 2C19*1*17 genotype, and a poor metabolizer with an ultrarapid metabolizing allele at 2C19 was prescribed fluoxetine 10 mg because his twin was comatose after a car accident:
I felt better, energized, then restless, no appetite, no sexual desire; gouged my lip then became aggressive, paranoid, violent, could not sleep, walked around thinking constantly about suicide. Tried to kill myself twice, tying a sheet around my neck, cutting my wrist, became depressed, and cried. I ran out of fluoxetine and felt like a ticking time bomb. I had no thoughts for consequences. Fearless, I challenged strangers to fight, punched out windows, threw a toolbox through windscreen and sped, running over street signs, crashed my truck; stood at the top of a bridge wanting to jump. I wrote messages on shattered windscreen. Wanting to die, I walked a long way to a friend’s house where I found a pistol, walked eight miles to my father’s house, talked to him for a few minutes. Felt very small, as if watching myself from above. I remember my dad, then the sound of a gun. No argument, no provocation. Don’t remember pulling it out of my backpack or pointing it. Couldn’t understand what had happened. What had I done? I wanted to shoot myself. I confessed immediately.