Antidepressant-induced akathisia-related homicides associated with diminishing mutations in metabolizing genes of the CYP450 family

Figures & data

Table 1 Drug metabolizing CYP450 phenotypes and polymorphic CYP450 alleles of importance for drug response

Phenotype	Genetic basis	Clinical consequences	Examples of alleles causing the phenotype	Examples of clinical consequences
UM	More than two active gene copies on the same allele, or increased expression of a single gene	Lack of response of the parent drug Increased ADRs due to increased metabolite or active drug production	CYP2C19*17 CYP2D6*1*2 x N (gene duplication/multiduplication)	CYP2C19: increased bleeding risk with clopidogrel CYP2D6: nonresponse of antiemetics, antidepressants and increased suicide risk ADRs after codeine and tramadol treatment
EM	Two functional alleles	Ordinary response	CYP2C9*1, CYP2C19*1, CYP2D6*1	Normal metabolism
IM	One defective allele or two partially defective alleles	Increased concentration of parent drug Decreased metabolite formation	CYP2C9*2, CYP2D6*10, CYP2D6*41	Reduced response to tamoxifen and to analgesic treatment
PM	Two defective alleles	Higher levels of the parent drug Increased risk for ADRs	CYP2C9*3, CYP2C19*2, CYP2C19*3, CYP2D6*4, CYP2D6*5	Increased ADRs Reduced response to analgesics and tamoxifen

Note: Reprinted from Biochemical and Biophysical Research Communications, vol 396, issue 1, M Ingelman-Sundberg, SC Sim, Pharmacogenetic biomarkers as tools for improved drug therapy; emphasis on the cytochrome P450 system, pages 90–94. Copyright 2010, with permission from Elsevier

Abbreviations: ADR, adverse drug reaction; UM, ultrarapid metabolizer; EM, extensive metabolizer; IM, intermediate metabolizer; PM, poor metabolizer.

Table 2 Drugs involved in these cases, with therapeutic windows and CYP450 attribution as metabolic substrates, inhibitors, and inducers

Drug	Therapeutic window	CYP450 metabolism	Enzymes inhibited	Enzymes induced
Alcohol		2E1^d	2E1 (acute)	2E1 (chronic)
Cannabis and its metabolites^Citation46^–^Citation49		2C9, 3A4	2C9, 3A4, 3A5	2C9
Ciprofloxacin		3A4	1A2^a, 3A4^a
Citalopram	30–130 ng/mL	2C19, 2D6, 3A4	2D6^c
Escitalopram	15–80 ng/mL	2C19, 2D6, 3A4	2D6^c
Estrogen		2C9 (minor), 3A4	2C19^b, 3A4^c
Fluoxetine	120–300 ng/mL (including norfluoxetine)	2C9, 2C19, 2D6, 3A4	1A2^c, 2C9^b, 2C19^b 2D6^a, 3A4^b, 2B6^b
Fluvoxamine	150–300 ng/mL	1A2, 2D6	1A2^a, 2B6^b, 2C9^b,
			2C19^a, 2D6^b, 3A4^b,
Hypericum				2C9 (long-term), 2C19, 3A4
Nortriptyline^Citation25^–^Citation28,Citation32^–^Citation36	70–170 ng/mL	2D6, 3A4	2C19, 2D6
Paroxetine	70–120 ng/mL	2D6, 3A4	1A2^c, 2B6^a, 2C9^c, 2C19^c, 2D6^a, 3A4^b,
Sertraline	10–50 ng/mL	2B6, 2C9, 2C19, 2D6, 3A4	1A2^c, 2B6^b, 2C9^b, 2C19^b, 2D6^e, 3A4^b
Serotonin (5HT)		2C9
Valerian^Citation37^–^Citation39			3A4
Valproate	50–100 μg/mL	Complex: 2A6, 2C9, 2C19	2C9, 2D6	Uncertain, possibly 3A4
Venlafaxine	195–400 ng/mL (including O-desmethylvenlafaxine	2C19, 2D6, 3A4	2D6^c
Zolpidem	90–325 ng/mL	1A2, 2C9, 3A4 (major)

Notes: Where not referenced, data is from Wynn et al.¹

a Potent inhibition;

b moderate inhibition;

c mild inhibition;

d other hepatic and extrahepatic pathways important;

e sertraline is a potent inhibitor at high concentrations (typically at doses > 200 mg/day); information about therapeutic window is from Baumann et al.¹⁸

Table 3 Information on subjects’ drug regimes, CYP450 genotypes, criminal acts, and outcomes for ten of those suffering violent akathisia

Subject number	Drug, dose and treatment duration	Genotypes	Circumstances of crime	Outcome
Gender	Reason for treatment	# of null, diminished or ultrarapid metabolizer alleles
Age
1 F 35	Nortriptyline (12.5 mg/day) superimposed on valerian Treated for distress due to husband’s drinking	2D6 *4/*41 2C9 *1/*2 2C19 *1/*17 One null allele Two diminished alleles One ultrarapid allele	Killed teenage daughter in toxic delirium after 3 days	Pleaded mental illness, misdiagnosed with schizophrenia and treated with more CYP450 substrates. Recovered on withdrawal but more drugs are still being prescribed on Tribunal orders with near fatal consequences
2 M 18	Fluoxetine (10 mg/day) 14 days then 4 days in withdrawal superimposed on cannabis use Treated because twin sister was comatose after a car crash	2D6 *5/*4 2C9 *1/*1 2C19 *1/*17 Two null alleles One ultrarapid allele	Violent akathisia for 14 days; killed father 4 days after subject ran out of pills	60-year sentence, wants to appeal Recovered on withdrawal
3 M 35	Paroxetine (20 mg/day) minimal alcohol Distressed by “on and off” relationship with mother of his child	2D6 *2/*4 2C9 *1/*2 2C19 *1/*2 Two null alleles One diminished allele	Stabbed former partner 30+ times after 11 weeks of akathisia on paroxetine Psychological blow automatism, no memory	Suspected of bipolar disorder before stopping paroxetine Convicted of murder Recovered on withdrawal
4 M 46	Paroxetine (40 mg/day) 40 weeks. Suicidal, but resumed and increased to 60 mg/day Anxiety about not making enough money to support family; insomnia and weight loss	2D6 *1/*41 2C9 *1/*1 2C19 *17/*17 One diminished allele Two ultrarapid alleles	Killed son in a manic-shift akathisia/delirium after 42 days on paroxetine and 20 days after its increase to 60 mg/day	Medical supervision Recovered on withdrawal
5 M 16	Fluoxetine (60 mg/day, valproate 1000 mg/day) Treated because depressed, in a group home, struggling at school, and girlfriend left	2D6 *1/*6 2C9 *1/*1 2C19 *1/*1 One null allele	Killed therapist in hospital after 11 weeks, in hospital for suicide attempts on sertraline, then on fluoxetine	14 years in jail for murder; wants to appeal Recovered on withdrawal
6 M 50	Initially fluoxetine then amitriptyline Valproate (800/mg day) throughout (polypharmacy) Then venlafaxine (300 mg/day) + valproate + zolpidem and/or zopiclone for 2 years Finally, withdrawal from venlafaxine while on a vitamin mixture containing serotonin, ciprofloxacin, and zolpidem (10 mg) taken repeatedly Treated because of distress over divorce.	2D6 *1/*2 2C9 *1/*1 2C19 *1/*2 One null allele	3 years of violent akathisia on polypharmacy. In withdrawal from venlafaxine (4 days), subject shot a stranger with friend’s gun; subject recalled nothing Homicide occurred in a state of somnambulism	Appeal by state against short sentence was unsuccessful Recovered on withdrawal
7 M 24	Sertraline, then escitalopram (10 mg/day) + hypericum (900 mg/day) caused a series of suicide attempts and assaults culminating in near lethal violence Treated for anxiety and illicit substance use	2D6 *1/*41 2C9 *1/*2 2C19 *1/*2 One null allele Two diminished alleles	Nearly killed partner after 2 months of uncharacteristic violence	12 years in jail for attempted murder: wished to appeal Recovered on withdrawal
8 F 26	Paroxetine (20 mg/day) followed by fluoxetine, sertraline, citalopram then venlafaxine (300 mg/day) for 2 years Treated for difficulties with in-laws	2D6 *2/*4 2C19 *2/*17 2C9 *1/*1 Two null alleles One ultrarapid allele	Several suicide attempts and two attempts to kill two children	Pleaded diminished responsibility to four charges of attempted murder, no jail time. Recovered on withdrawal
9 F 52	Paroxetine (to 60 mg/day) then citalopram, fluoxetine then venlafaxine 300 mg/day) and intermittent metoclopramide as needed, tramadol as needed, diazepam 5 mg as needed, conjugated estrogens (Premarin) 0.625 mg, pravastatin 40 mg, sometimes altovastatin, irbesartan (300 mg/day), tenormin (12.5 mg/day), valacyclovir for shingles, seretide, various antibiotics, penicillin, cephalexin, erythromycin, celecoxib (200 mg ad lib), oroxine (100 mg/day), various antibiotics, flu vaccination. Treated for harassment at work	2D6 *4/*4 2C9 *1/*1 2C19 *1/*1 Two null alleles	Tried to kill two children after 3 years of akathisia on all SSRIs, against a background of polypharmacy involving up to ten drugs at a time	Hospitalized: venlafaxine for another year until unassisted withdrawal Further episodes of akathisia with tramadol, simvastatin, conjugated estrogens on their own Recovered from akathisia on withdrawal but never worked again
10 F 25	Citalopram (dose unknown), then venlafaxine superimposed on heavy cannabis use. Treated for marital distress	2D6 *2/*4 2C9 *1/*2 2C19 *1/*1 One null allele One diminished allele	Personality changed to aggressive and suicidal; subject jumped in front of train with child and lost custody for years	Subject was switched to venlafaxine on which she continued to make suicide attempts for 4 years until withdrawal and full recovery

Note: All subjects were tested at Healthscope Molecular (Melbourne, Australia) except Subject 5, who was tested for the same alleles at Genelex (Seattle, WA, USA).

Abbreviation: SSRI, selective serotonin reuptake inhibitor.

Figure 1 Prevalence of individuals with different numbers of variant CYP450 alleles in two groups: akathisia subjects and randomly selected primary care patients.

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