Association of quetiapine with ischemic brain stem stroke: a case report and discussion

Introduction

Atypical antipsychotics (AAPs) are approved by the US Food and Drug Administration (FDA) for the treatment of schizophrenia and bipolar disorder. Since the health regulatory agency of Canada (2002), the FDA (2003), and the European Medicines Agency (2004) reported an increased risk of cerebrovascular adverse events (CVAEs) from olanzapine and risperidone in clinical trials of elderly demented patients, there have been concerns about the risk of CVAEs associated with AAPs, and recent guidelines emphasize the importance of generating evidence for AAPs [Shin et al. 2013; Barnes, 2011].

In this article, an ischemic pontine stroke case probably related to quetiapine use is presented. Discussion of the case is of great importance because there are very limited data on the risk of CVAEs associated with the use of quetiapine,

Case report

A 42-year-old male patient, with a history of bipolar disorder, which had been treated for 2 months with quetiapine 300 mg daily, was admitted to the emergency service with complaints of double vision, inability to move his eyes, balance impairment, sensory defects, and difficulty walking on his own. He later developed dysarthria. As reported by the patient, these complaints developed after a sudden fall and a 1-h loss of consciousness. He had never had any neurological complaints before. On examination, the patient was alert and oriented to person, place, time, and situation. He was noted to have left third and sixth cranial nerve palsy, dysmetria, and prominent horizontal nystagmus. He was unable to complete the heel–toe walking test because of ataxia. There was ataxia on finger–nose testing as well. There was otherwise no motor-sensory deficit or lateralization. He was not on warfarin at time of admission.

The diffusion-weighted magnetic resonance imaging (MRI) examination was consistent with ischemic regions in the right pontine area. Head and neck computed tomography-angiography and MRI-angiography examinations were within normal limits. His vital signs were within normal ranges. Transesophageal echocardiography examination was normal as was 24-h Holter monitoring. The body mass index of the patient was 23 (normal range 18–24). Routine laboratory investigations revealed raised levels of total cholesterol 6.5 mm/L (normal range 0–5.2 mm/L), and triglyceride 2 mmol/L (normal range 0.5–1.9 mmol/L). Complete blood count, erythrocyte sedimentation rate test, electrolytes, liver, renal, and thyroid function tests, hemostasis panel, genetic analyses for clotting factors, rheumatoid factors, and homocysteine, folate, and methyl malonic acid levels were all normal.

He had a past history of a peptic ulcer and he had been smoking cigarettes. There was no relevant family medical history. Bipolar disorder had been diagnosed 4 months previously and had been well controlled on quetiapine 300 mg/day, which he had taken for 2 months. He had not been treated with any other psychotropic medication.

The patient was admitted to the neurology service. Coraspin 300 mg/day, atorvastatin 10 mg/day, and esomeprazol 40 mg/day treatment were initiated. Quetiapine treatment was stopped. By the end of the second week, on examination, there was only partial limitation of lateral movement on his left eye. The cholesterol and triglyceride levels were normal at the fourth week of treatment. The patient gave up smoking cigarettes by the end of the second month.

Discussion

Ischemic stroke has been reported to be highly fatal among CVAEs and has been reported as a major cause of death and disability worldwide [Donnan et al. 2008]. The development of ischemic brainstem stroke in this patient after initiation of quetiapine monotherapy for bipolar depression may suggest that quetiapine has the capacity to induce stroke at least in patients with a history of mood disorders. To the best of our knowledge, this is the first case report of ischemic pontine stroke associated with the use of quetiapine.

There are conflicting findings regarding the cerebrovascular safety and any such association of AAPs [Mazzucco et al. 2008; Sacchetti et al. 2010]. Data from a clinical trial using quetiapine to treat behavioral and psychological symptoms of dementia showed no increased risk of CVAEs compared with placebo [Tariot et al. 2006; Zhong et al. 2007]. However, there are no available data in these studies, both on the odds ratios (ORs) and the confidence intervals (CIs). Another clinical trial also suggested that olanzapine could be a safe medication in the elderly [Moretti et al. 2005]. A recent population-based, case-crossover study revealed nearly a four-fold increase in the risk of ischemic stroke related to the use of all AAPs [Shin et al. 2013]. According to the findings of this study, risperidone and quetiapine showed similar increased risk profiles in geriatric patients regardless of the presence of dementia. In this study, a total of 1601 cases of ischemic stroke with a mean age of 75.6 (± 6.7) years were identified, of which 933 (58.3%) were female. An increased risk of ischemic stroke was associated with the use of risperidone (aOR = 3.5, 95% CI 3.3–4.6) and quetiapine (aOR = 2.7, 95% CI 2.0–3.6) during the 30 days prior to stroke: however, no significant risk was observed with olanzapine (aOR = 1.2, 95% CI 0.7–2.0). The increased stroke risk in demented patients, assessed within 30 days after exposure, was also observed with olanzapine. However, the sample of olanzapine users was small and underpowered. Quetiapine was associated with a 2.7-fold increased risk of ischemic stroke, supporting a previous cohort study which showed a 2.1-fold increased risk compared with olanzapine [Shin et al. 2013]. These findings were consistent with previous research [Douglas and Smeeth, 2008; Sacchetti et al. 2008].

Although several hypotheses have been suggested [Smith and Beier, 2004; Wu et al. 2013b], the biological mechanisms responsible for a possible increased risk of ischemic stroke have remained unknown. Differences among these AAPs have been suggested to be associated with their chemical class, structure, and mechanism. In previous studies, differences in safety profiles related to hyperprolactinemia and hypotension among risperidone, quetiapine and olanzapine have been demonstrated [Shin et al. 2013]. Another study suggested that drug-induced hyperprolactinemia, which may promote platelet aggregation, could increase the risk of ischemic stroke [Smith and Beier, 2004]. Orthostatic hypotension also has been seen with AAP use and may explain the fact that direct cardiovascular effects are related to increased risk of ischemic stroke [Gardner et al. 2005].

Findings of a recent study [Wu et al. 2013a] suggested that the use of antipsychotics with a high binding affinity to M1 muscarinic and α2 adrenergic receptors is associated with a greater risk of stroke than the use of other types of antipsychotics. Moreover, this study showed that stroke risk with antipsychotic use is in a dose-related relationship [Wu et al. 2013a].

Peripheral arterial compliance (PAC) is a measure of elasticity of the arteries that has been found to be a robust predictor of prevalent arteriosclerosis as well as incident stroke, but effects of AAPs on PAC are unknown. According to the findings of recent studies, patients taking either quetiapine or risperidone had significantly lower arterial compliance than controls, suggesting that antipsychotics might be an additional risk factor for reduced PAC [Koola et al. 2012]. Recent studies suggest that the presence of psychiatric diagnoses is also associated with reduced PAC. Although not conclusively proven, low PAC in psychiatric patients may be secondary to sedentary life style, poor nutrition, smoking, metabolic syndrome, and aberrant cytokines. There is a growing body of evidence showing the association of cytokine abnormalities and psychiatric disorders [Koola et al. 2012].

Furthermore, bipolar disorder is a major psychiatric disorder that is associated with several medical conditions contributing to substantial morbidity and mortality [Wu et al. 2013b; Kemp et al. 2010]. Previous studies have demonstrated common medical illnesses comorbid with bipolar disorder, including obesity, hyperlipidemia, hypertension, and diabetes mellitus, all of which are recognized as risk factors for stroke [Kemp et al. 2010]. Several factors may explain this phenomenon, including worse medication side effects, unhealthy life-style behaviors, poorer access to healthcare services, socioeconomic status, and biologic susceptibility. These studies state that it is often unclear whether a medical disorder is truly comorbid, a consequence of treatment, or a combination of both [Kemp et al. 2010; Evans-Lacko et al. 2009; Krishnan, 2005]. When the current authors reviewed the studies discussing the relationship between mood disorder and stroke, several reported a possible relationship between major depressive disorder and stroke. One study found that the presence of depressive symptoms is a strong risk factor for stroke in men but not in women [Bos et al. 2008]. Another study showed that depressive symptoms were an independent risk factor for the incidence of stroke/transient ischemic attack in individuals, older than 65 years of age [Salaycik et al. 2007]. Other studies have shown that depressive symptoms predicted stroke, and that a significant relationship exists between depressive symptoms and stroke mortality [Lin et al. 2007]. This study showed that patients with bipolar disorder comorbid with alcohol or substance dependence had a higher risk of stroke. Patients with bipolar disorder are more likely to have diabetes, hypertension, hyperlipidemia, and coronary heart disease, which is consistent with previous studies [Hsieh et al. 2012]. It has been well documented that the incidence of stroke may be associated with these four illnesses and that the incidence of stroke is higher in men and older individuals [Lin et al. 2007]. Patients with bipolar disorder were at a significantly higher risk for stroke and poststroke death from any cause after adjusting for demographic, socioeconomic, and comorbid medical variables.

It is recommended that clinicians should monitor and manage patients with bipolar disorder carefully, with the aims of preventing stroke and decreasing mortality. The survey of vascular risk factors and regular neurological examination may be needed for patients with bipolar disorder, especially for older patients with physical comorbidities.

This case report provides support of previously published studies suggesting that even brief exposure to antipsychotics can result in adverse health outcomes [Wang et al. 2012]. Indeed, multiple factors may increase the chance of a stroke. Psychiatric diagnoses and second-generation antipsychotics may contribute to cardiovascular risk, myocardial infarction, and stroke. For an exposure to trigger stroke, other contributing causes are usually present. Among older patients already at high risk, exposure to antipsychotics might be an important factor precipitating stroke [Shin et al. 2013].

Weighing the risks and benefits of antipsychotic treatment is particularly important for providers treating patients with multiple comorbid risk factors for stroke. The clinical implication is to start antipsychotics treatment at low dosages and to monitor closely the side effects in the initial treatment, particularly in older individuals, and in the presence of dementia.

Based on the data available so far, risperidone and quetiapine should be prescribed with caution regardless of the presence or absence of dementia. Olanzapine may be more acceptable in nondemented geriatric patients associated with the risk of ischemic stroke, although wider consideration of all potential risks (e.g. greater weight gain which can, in turn, be associated with additional risks to health) and benefits should be considered.