Depression, antidepressant treatment and the cardiovascular system

Depression and cardiovascular disease (CVD) may become the two biggest disease burdens by 2020 and their association has attracted significant research interest. Healthy cardiac activity involves a high degree of beat-to-beat variability, mediated by the parasympathetic (vagus nerves) and sympathetic nervous system that slows and accelerates heart rate, respectively. Reduced heart rate variability (HRV), characterised by reduced vagal and increased sympathetic influences to the heart, is a robust predictor of fatal or near-fatal cardiac arrhythmia, even in relatively healthy individuals without a prior history of CVD (1). A random sample of 900 subjects from a population study of 14 672 men and women without coronary heart disease (CHD) (1) reported that low HRV measured from a 2-min electrocardiogram (ECG) was associated with an adverse cardiovascular risk profile and elevated risk of incident CHD and death from several causes 6 years later. For instance, relative risks of CVD death in participants with measures of low HRV ranged from 1.98 to 3.44, suggesting that reduced HRV may be a sensitive indicator of future mortality that may precede the manifestation of CVD. Increased heart rate variability may help to foster calm behavioural states and facilitate social engagement (2). HRV is an index of beat-to-beat changes in heart rate and may reflect an individual’s capacity to engage and interact with their environment. Although research has traditionally focused on paired antagonism between parasympathetic versus sympathetic innervation to the heart, the polyvagal theory (2) distinguishes between the myelinated vagus which facilitates facial expression, vocalisation and listening (i.e. social communication) from the unmyelinated vagus which is linked to immobilisation behaviours including feigning death, bradycardia, vasovagal syncope and behavioural shutdown. This theory highlights a bidirectional relationship between spontaneous social engagement and bodily states that is mediated by the myelinated vagus. Patients with depression display significant social impairments including lack of facial expressiveness and deficits in emotional prosody. Patients may also display reduced HRV, although many studies have focused on patients with CVD (3). The polyvagal theory (2) suggests that these social impairments and autonomic dysregulation such as reduced heart rate variability may be linked. (See (4) for a more general review of the association between depression and abnormalities in the cardiovascular system. ) It is therefore possible that successful treatment of depression may also alleviate cardiovascular impairment. A recent meta-analysis examined the impact of depression and a variety of antidepressant treatments on HRV (3). Depressed patients have reduced HRV – this was particularly apparent when using nonlinear measures of HRV – and further HRV decreases with increasing depression severity. Unlike the majority of prior studies that had been conducted in cardiac patients, this study focused on patients without CVD, highlighting the need for clinicians to be mindful of the cardiovascular system in patients without such history. It was also found that while tricyclic antidepressants (TCAs) decreased HRV, serotoninreuptake inhibitors (SSRIs) and other antidepressants including mirtazapine and nefazodone had no significant impact despite patient response to treatment. Although these findings re-inforce the need for caution over prescribing TCAs, particularly in patients with CVD, they indicate that SSRIs have relatively benign HRV-mediated cardiovascular effects (5). These findings are further supported by a recent prospective study (6) on 14 784 community-dwelling adults without a history of CVD, which reported an elevated risk of fatal and non-fatal CVD events (CVD events included CVD death, non-fatal myocardial infarction, coronary surgical procedures, stroke and heart failure) in users of tricyclic (TCA, n = 324) but not SSRI medications (n = 299) over an 8-year follow-up. The authors reported a 35% increased risk in CVD events in TCA users after accounting for a variety of covariates, including depression and anxiety. Other covariates included age, sex, socioeconomic group, marital status, physical activity, smoking, alcohol, body mass index, CVD medication and hypertension. The adverse effects of TCAs probably relate to increased anticholinergic effects at the sinoatrial node of the heart, involving blockade of the muscarinic acetylcholine receptors. Although tricyclic antidepressants are associated with greater affinity to muscarinic receptors, SSRIs are more benign, with the exception of paroxetine, which has considerable antimuscarinic potency (7). Blockade of these receptors leads to decreased parasympathetic activity, disinhibition of sympathetic nervous system activity, tachycardia (rapid heart rate) and reduced HRV. However, others have recently reported that while HRV is reduced in depression, these effects are primarily driven by antidepressants – including TCAs,