In England the adult psychiatric morbidity survey of 2007 found the weekly community prevalence of a depressive episode to be 2.3% and that for generalized anxiety disorder (GAD) 4.4% [Bebbington et al. 2009
]. It is therefore not surprising that depression and anxiety are two of the most common disorders managed by general practitioners (GPs). The vast majority of depression is treated solely in primary care with only about one in four or five patients with depression referred to secondary mental health services [NICE, 2010
]. In the adult psychiatric morbidity survey 24% and 13% of people with depression and GAD respectively had spoken with their GP in the last 2 weeks and 65% and 52% within the last year. This results in a considerable burden on GPs with a UK primary care survey finding that 7.2% of consecutive consultations were for probable depression [Ostler et al. 2001
]. In the UK there has been a significant focus on improving treatment and services for people with depression and anxiety disorders, with the National Institute for Health and Clinical Excellence (NICE) recently updating their guidance on the management of depression [NICE, 2010
] and GAD [NICE, 2011
]. Much of this focus has been on increasing the availability of psychological services, but pharmacological therapies are still a core component of treatment for both conditions, particularly for more severe presentations or when psychological treatments have been ineffective.
The mainstay of pharmacological treatments for depression and GAD are antidepressants, and in the UK 95% of all prescriptions for antidepressants are issued by GPs [Henry, 1993
; NICE, 2010
]. In the UK, prescribing of antidepressants in primary care has been increasing steadily over the last decade, which has been explained mainly by an increase in the proportion of patients receiving long-term treatment [Moore et al. 2009
]. In England during the 3 months to September 2011, over 11 million prescriptions for antidepressants were prescribed in primary care [National Health Service Business Services Authority, 2011
] making them one of the most commonly prescribed classes of drugs [National Health Service Information Centre for Health and Social Care, 2010]. Selective serotonin reuptake inhibitors (SSRIs) are recommended by NICE as first-line pharmacological treatment for both depression and GAD and the dual action antidepressants serotonin and noradrenaline reuptake inhibitors (SNRIs) are among the second-line treatments [NICE, 2010
]. Drug safety is one of the key considerations when prescribing in primary care and this is particularly applicable in conditions such as depression and anxiety when there is a risk of suicide by antidepressant overdose among other means and the disorders are often accompanied by other psychiatric and medical comorbidities. However, the safety of antidepressants has been called into question over the last decade. The UK Medicines and Healthcare Products Regulatory Agency (MHRA) has issued guidance on a number of safety issues, including suicidal behaviour [MHRA, 2007
], discontinuation reactions [MHRA, 2004
], use in pregnancy [MHRA, 2010a
], risk of fracture [MHRA, 2010c
], cardiotoxicity and toxicity in overdose [MHRA, 2004
] related to antidepressants. These warnings have applied to some of the most commonly prescribed antidepressants in primary care. For example, the most recent guidance regarding QT prolongation [MHRA, 2011
] relates specifically to citalopram, the most commonly prescribed SSRI in the UK [National Health Service Business Services Authority, 2011
], and its related compound escitalopram. These recommendations are potentially alarming for GPs and patients and may undermine the confidence in antidepressants in general. However, it is important that the safety data relating to antidepressants are fully understood in the context of treating depression when, for many patients, several different antidepressants have been prescribed before an effective treatment is found. One important group of antidepressants for which there have been safety concerns in the past is the SNRIs. There is evidence to suggest that the confidence of GPs in the safety of the SNRI venlafaxine may have been eroded following the MHRA urgent safety restriction (USR) issued in 2004 [MHRA, 2004
] after which prescribing rates diminished over the next year [McAllister-Williams et al. 2006
]. Venlafaxine has been licensed for the treatment of depression in the UK since 1994 and had been increasingly prescribed by GPs and specialists as a second-line treatment for depression. The USR related to potential toxicity in overdose and it restricted the initiation of venlafaxine to mental health specialists and gave new contraindications in patients with heart disease. In 2006, after a reexamination of the safety evidence and taking into account new epidemiological data, the MHRA released updated guidance on the prescribing of venlafaxine [MHRA, 2006
]. This new guidance removed the recommendation for specialist initiation of venlafaxine along with some of the contraindications, and requirement for baseline electrocardiogram (ECG) monitoring, again allowing its initiation by GPs in primary care. Despite this change of guidance in 2006, prescribing of venlafaxine in primary care has since remained static [Ilyas and Moncrieff, 2012
], and against a background of increasing antidepressant use, it may be conjectured that GPs are still wary of prescribing venlafaxine in primary care. In 2005 a second SNRI, duloxetine, was licensed for the treatment of depression. We speculate that many GPs may take the view that, as an SNRI, this may also carry a higher risk of cardiotoxicity or other toxicity than other antidepressants.
This paper aims to review the data examining mortality associated with overdose of venlafaxine and duloxetine, including the data examining suicidality and cardiovascular safety. Based on this evidence, recommendations can then be made as to their suitability for use in primary care from a perspective of these major safety issues. The review will take the following structure:
- (1) Mortality due to overdose of venlafaxine and duloxetine. The evidence of how these data are synthesized and analyzed using the fatal toxicity index (FTI) will be reviewed. This will be followed by a review of deaths from overdose using case series which are easy to understand and give further information on the safety of antidepressants.
- (2) A brief review of cardiovascular safety of the SNRIs will be presented.