First-degree relatives with behavioural adverse effects on statins

Abstract

Irritability, aggression and other adverse behavioural effects have been associated with the use of statins (3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors) and other drug classes. A number of studies have also linked low cholesterol with aggression and violence. This paper presents the cases of two first-degree male relative patients (father and son) identified by self-referral to the University of California in San Diego Statin Effects Study. Both patients experienced behavioural adverse effects on statins including irritability and aggression, however neither patient recognised a significant change in their behaviour. This may be the first report of behavioural adverse effects manifested on statins by first-degree male relatives, which may suggest possible familial/biological predisposition. These cases also highlight the issue of externalisation by patients of the origin of interpersonal discord, which may serve as an obstacle to adverse effects reporting and lead to negative outcomes for patients, and for those around them.

Background

Adverse behavioural changes including irritability/aggression have been reported with a number of drug classes. These include alcohol,¹ prescription psychiatric drugs,^2–5 steroid hormone-altering agents (anabolic steroids, retinoids),^{6 7} varenicline⁸ and antimalarial drugs.^{9 10} Low cholesterol has been linked to violence/aggression in a number of studies,^11–14 and some reports have linked statin cholesterol-lowering drugs to behavioural adverse effects.^{15 16} Statins (3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors) are among the best selling prescription drugs.¹⁷

Understanding potential effects of these drugs is important. We present a pair of cases in which behavioural adverse effects were manifested on statins by first-degree male relatives (father and son).

Case presentation

Patients were identified by self-referral to the University of California in San Diego Statin Effects Study. Both patients described here gave informed consent. Both shared information on the drug use and timing to onset of adverse symptoms. Both gave permission for their family members to give input on their observations on the behavioural change.

Patient 1 is a 70-year-old married male. The patient had no significant medical history and received no significant medication until age 62, when he underwent double coronary artery bypass grafting (CABG). Following CABG, the patient initiated medication comprising atorvastatin, ramipril, perindopril and aspirin. No risk factors for statin-associated adverse events (AEs) were identified in this patient.¹⁸

At approximately 3 months of medication use, the patient’s wife observed that the patient had become increasingly irritable and aggressive, stating that ‘nothing made him happy; he was permanently angry’. She described him as having a ‘permanent scowl’ on his face and found him very quick to argue. The patient’s wife reported that these behavioural changes constituted a marked departure from the patient’s usual easygoing personality. Initially, she assumed these behavioural changes to stem from the stress of undergoing CABG surgery. As for the patient, he did not recognise any significant behavioural difference in himself and instead perceived his wife as being unreasonable; ‘I kept saying, It’s you being difficult. Not me’.

At approximately 1 year after atorvastatin initiation, the patient reported non-behavioural adverse effects comprising arthralgia, myalgia and myopathy to his physician. The physician responded by switching the patient from atorvastatin to simvastatin and the patient remained on simvastatin therapy for approximately 1 year, during which time behavioural and muscular adverse effects were neither resolved nor reduced in severity.

The personality change and impaired conation produced a negative impact on family and social function over the 2 years he remained on statins, with his wife stating ‘he didn’t want to go out anywhere and if we did, nothing would please him’. His relationship with his wife became increasingly difficult, with his wife reporting ‘I didn’t know how much more of this I could take from him’.

The patient elected to discontinue treatment with statins at 2 years. At approximately 5 weeks following discontinuation, the patient’s wife reported recognition that the patient’s ‘personality was coming back’ and that she noticed a ‘definite change in his behaviour and wellbeing’. Muscle symptoms, as well as behavioural alterations, reversed. The patient did not rechallenge with statin therapy and presently receives no cholesterol-lowering therapy. He has experienced no behavioural or muscular adverse effects since discontinuation of statin treatment.

Patient 2 is a 40-year-old married male. He has a history of stage 1 hypertension controlled by an ACE inhibitor since late 2009. In late 2010, a lipid panel for the patient indicated hyperlipidaemia and the patient initiated atorvastatin. Two risk factors associated with adverse effects on statin therapy have been identified for this patient,¹⁸ comprising hypertension and family history of AEs associated with use of the statin drug class. The patient’s wife reports his usual personality as being calm, even-tempered, and soft-spoken.

In the case of patient 2, behavioural adverse effects, representing a marked departure from prestatin state, were observed within 2–3 days of statin initiation. The patient’s wife reported that the patient became severely irritable over minor issues and was quick to become severely angry to the point of shouting. During one of these arguments, the patient’s wife reported that she ‘began to feel scared; it was like he was a different person’. The patient also reported a specific incident in which he was wrongly accused of not buying a bus ticket, ‘I exploded in response to the accusation. When another passenger joined in, I shouted and stared him down, too’. When questioned retrospectively about this incident, the patient reported, ‘I’m normally the kind of person who tries to help resolve arguments. But on that occasion, I came extremely close to physically lashing out’. The patient also pointed out that ‘I could not detect my own increased aggression. At the time I felt as if everyone around me was acting unreasonably, forcing me into retaliating. I felt completely justified’.

The patient was able to detect concurrent signs of depression. He described these feelings to his mother, who reminded him of the adverse effects experienced by his father while receiving post-CABG medication. Patient 2 had heard of his father’s experience on statin therapy but had assumed it to be associated with the stress of having undergone major surgery and not statin use. Nevertheless, patient 2 discontinued statin therapy and all symptoms of irritability, aggression and depression resolved completely within 2 to 3 days. Remaining unconvinced that statins were linked to these adverse behavioural effects, patient 2 rechallenged with atorvastatin in December of 2010. Within 3 days, the patient experienced a noticeable increase in difficulty in dealing with his wife coupled with feelings of depression. The patient discontinued statin use on day 4 and has not used them since. All behavioural adverse effects resolved within 2 days. The patient has since switched to niacin therapy and both the patient and his wife report no recurrence of adverse effects.

Table 1 summarises information including drug and dose, lipid panel data prior to treatment, time course of onset and resolution of clinically evident irritability, risk factors for statin-associated adverse effects, manifestations, consequences and personal versus family recognition of statin-associated adverse effects.

Table 1.

Characteristics of patients 1 and 2

		Case 1	Case 2
Sex		Male	Male
Age at first occurrence		62	39
Education		High school	Postgraduate
Lipid panel prior to statin initiation	LDL-C	NM	120 mg/dl
	HDL-C	NM	50 mg/dl
	TG	NM	140 mg/dl
	TC	NM	220 mg/dl
Statin drug #1		Atorvastatin 20 mg/day	Atorvastatin 20 mg/day
Statin drug #2		Simvastatin 20 mg/day	Atorvastatin 20 mg/day (rechallenge)
Time course to noted onset #1		Approx. 3 months	2–3 days
Time course to noted onset #2		NA*	3 days
Time course to first noted improvement #1		NA*	2–3 days
Time course to first noted improvement #2		4 to 5 weeks	2 days
Time course to full improvement #1		NA*	2–3 days
Time course to full improvement #2		4 to 5 weeks	2 days
Risk factors for adverse effects		None	Hypertension; family history of statin-associated AEs
Manifestations		Irritability	Irritability
		Aggression	Aggression
		Depression	Depression
		Conative impairment
		Myalgia
		Arthralgia
		Myopathy
Consequences
Personal versus family recognition (at the time of symptoms)		Personal: Non-behavioural AEs only	Personal: Depression only
		Family: All AEs recognised by spouse	Family: Irritability and aggression
Personal narrative comments regarding case (retrospective)		I kept saying, ‘It’s you being difficult. Not me.’	I was ready to lash out over something so tiny.
			I could not detect my own increased aggression. At the time I felt as if everyone around me was acting unreasonably, forcing me into retaliating in this way. I felt completely justified.
Family members’ narrative comments regarding case		Nothing made him happy; he was permanently angry.	I began to feel scared; it was like he was a different person.
		He had a permanent scowl on his face.
		He didn’t want to go out anywhere and if we did, nothing would please him.
		I didn’t know how much more of this I could take from him.

AE, adverse event; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; NM, not measured; TC, total cholesterol; TG, triglycerides.

^*Patient 1 did not have a wash-out period between use of statin 1 and statin 2; only data relating to AE resolution following discontinuation of statin 2 are available.

Discussion

To our knowledge this is the first report of behavioural adverse effects manifested on statins by first-degree male relatives (father and son). Both patients were exposed to the same statin dosage and both patients exhibited behavioural adverse effects comprising elevated irritability, increased propensity for aggression and onset of depression. The father additionally experienced conative impairment and non-behavioural adverse effects comprising myalgia, arthralgia and myopathy. Features indicative of probable causal relation to statin usage include occurrence on drug, resolution off, recurrence in the patient who rechallenged, previous reports of similar problems with this drug class,¹⁵ concurrent development of other recognised (muscle) adverse effect in one of the patients (with concurrent resolution on discontinuation), and biological plausibility.^{11 17–19} This is buttressed by a sizeable literature linking lower native cholesterol to higher violence and aggression/behavioural disturbance in humans, as well as in non-human primates.^{11–13 19–23}

While behavioural side effects have previously been reported on statin therapy, these cases are of interest because they occur in first-degree relatives, suggesting possible familial vulnerability.

Additionally these cases share in common that both patients perceived the increased arguments and social difficulties at the time they received statin therapy to be the result of unreasonable behaviour by those around them. It required the resolution of these problems with drug discontinuation (bolstered in one by recurrence with rechallenge), coupled with reflection on their actions, to permit the inference that the source of the increased discord rested with them.

Other evidence underscores this key point: persons experiencing behavioural adverse effects may interpret their own lack of agreeableness, or short temper, as others’ greater provocation. Many reports of behavioural adverse effects in our statin effects study have shared this theme. Additionally, such findings have been reported in a range of other settings. These include depression and its pharmacological redress²⁴; premenstrual dysphoria and its resolution²⁵; and the observation that ‘problem physicians’ disproportionately report ‘problem patients’.²⁶ In each instance persons who are less agreeable or more short-tempered interpret disagreeableness and provocation from others to be greater. Indeed, criminal offenders characterised by repeat non-premedidated actions commonly perceive their own aggressing to be a justified response to provocation.

These case reports share limitations common to all case reports/case series. Findings rely on self-report. However concerns about bias and attribution are somewhat reduced by these subjects’ lack of awareness of any hypothesis linking low/lowered cholesterol to irritability at the time they observed and reported these effects in themselves; by concordance with other patients’ reports; and by dechallenge, and in one case rechallenge support and a compatible literature. Indeed, these cases adhere to Naranjo criteria for probable or definite drug adverse effect causality.²⁷ These cases have no necessary implications for usual effects of statins on behaviour. Nonetheless, adverse effects of drugs are important to the individuals who experience them, irrespective of whether the drug produces similar effects on average, and even if it produces opposite direction usual effects.^{28 29}

These findings extend prior reports of behavioural adverse effects on statins, suggesting the possibility of familial/biological predisposition. They highlight an underemphasised issue in behavioural adverse effect study: that of externalisation by patients of the origin of interpersonal discord. This consideration must be born in mind in approaches for behavioural AE surveillance, in the statin setting and beyond. Failure of patients to recognise adverse personality change in them has potential implications. Such failure can serve as an obstacle for reporting, leading behavioural adverse effects to be under recognised. Such failure may serve as an obstacle to rectifying the problem, with adverse implications to family, social and professional function, and to negative outcomes for patients, and those around them.

Learning points.

• ▶Irritability, aggression, and other adverse behavioural effects have been associated with statin use.
• ▶Low cholesterol has been linked to violence and aggression in a number of studies.
• ▶Patients experiencing adverse behavioural effects, on statins as in other settings, may externalise the origin of interpersonal discord.
• ▶For patients and healthcare providers alike, lack of awareness of behavioural adverse effects associated with statin use can serve as an obstacle for reporting and for resolution of negative outcomes for patients and those around them.