Risk of suicide during treatment with venlafaxine, citalopram, fluoxetine, and dothiepin: Retrospective cohort study

The University of Warwick, Coventry, England, United Kingdom
BMJ (online) (Impact Factor: 17.45). 03/2007; 334(7587):242. DOI: 10.1136/bmj.39041.445104.BE
Source: PubMed


To compare the risk of suicide in adults using the antidepressant venlafaxine compared with citalopram, fluoxetine, and dothiepin.
Retrospective cohort study.
UK General Practice Research Database.
219,088 patients, aged 18-89 years, who were prescribed venlafaxine, citalopram, fluoxetine, or dothiepin from 1995 to 2005.
Completed suicide and attempted suicide.
Venlafaxine users had a higher burden of risk factors for suicide, including previous suicide attempts and proxies for severe depression or depression that was difficult to treat. In the analysis for completed suicides, unadjusted and adjusted hazard ratios for venlafaxine compared with citalopram were 2.44 (95% confidence interval 1.12 to 5.31) and 1.70 (0.76 to 3.80), for venlafaxine compared with fluoxetine were 2.85 (1.37 to 5.94) and 1.63 (0.74 to 3.59), and for venlafaxine compared with dothiepin were 2.54 (1.07 to 6.02) and 1.31 (0.53 to 3.25). Compared with other study drugs, venlafaxine was also associated with an increased risk of attempted suicide, but adjustment for measured confounders substantially reduced the hazard ratios.
Venlafaxine use was consistently associated with higher risk of suicide compared with citalopram, fluoxetine, and dothiepin. Venlafaxine users had a higher burden of suicide risk factors, however, and adjustment for measured confounders substantially reduced the excess risks. Since the secondary data used in this analysis allowed only indirect and partial measurements of potential confounders, it is possible that residual confounding explains much, if not all, of the observed excess risk.

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Available from: Neil Roskell, Nov 07, 2014
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    • "As might be anticipated, the patients who were treated with venlafaxine in the ONS data were found to have a higher burden of suicide risk factors than those prescribed SSRIs [Mines et al. 2005]. To try to compensate for the inherent risk factors using data from the UK General Practice Research Database (UKGPRD), Rubino and colleagues adjusted the hazard ratios for venlafaxine versus fluoxetine, citalopram and dothiepin (dosulepin) using proxies for severity of depression such as previous suicide attempts [Rubino et al. 2007]. Once these confounders had been adjusted for, the hazard ratios were substantially reduced [from 2 "
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    ABSTRACT: Depression and anxiety disorders are among the most common disorders treated by general practitioners (GPs) in the UK. Since both disorders are associated with a significantly increased risk of suicide, including with antidepressant overdose, the safety of antidepressants in overdose is of paramount importance. Numerous updates relating to antidepressant safety have been issued by regulators in the UK which may have eroded GP confidence in antidepressants. Venlafaxine, a serotonin nor adrenaline reuptake inhibitor (SNRI) had primary care prescribing restrictions placed on it in 2004 due to concerns about cardiotoxicity and mortality in overdose. Although a review of the evidence led to a reversal of the majority of restrictions in 2006, evidence suggests GPs may still be cautious in their prescribing of venlafaxine and possibly other SNRI antidepressants for patients with depression and anxiety disorders. This paper reviews the evidence pertaining to the safety of SNRI antidepressants from a perspective of cardiovascular safety and overdose. The currently available evidence suggests a marginally higher toxicity of venlafaxine in overdose compared with another SNRI duloxetine and the selective serotonin reuptake inhibitors (SSRIs), although this may be related to differential patterns of prescribing in high-risk patients. Based on this review SNRIs have a positive risk benefit profile in the treatment of depression and generalized anxiety disorder in primary care, especially as second-line agents to SSRIs.
    Therapeutic Advances in Psychopharmacology 06/2013; 3(3):151-61. DOI:10.1177/2045125312472890 · 1.53 Impact Factor
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    • "Another explanation might be possible differences in prescribing practice of VEN compared with SSRIs. VEN may be more often prescribed to patients with prior prescriptions of another antidepressant drug [51] [52]. With regard to VEN toxicity, possible physiological drug effects also have to be considered. "
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    ABSTRACT: Venlafaxine (VEN) is an antidepressant drug mainly metabolized by the cytochrome P450 (CYP) enzyme CYP2D6 to the active metabolite O-desmethylvenlafaxine (ODV). VEN is also metabolized to N-desmetylvenlafaxine (NDV) via CYP3A4. ODV and NDV are further metabolized to N,O-didesmethylvenlafaxine (DDV). VEN is a racemic mixture of the S- and R-enantiomers and these have in vitro displayed different degrees of serotonin and noradrenaline reuptake inhibition. The aim of the study was to investigate if an enantioselective analysis of VEN and its metabolites, in combination with genotyping for CYP2D6, could assist in the interpretation of forensic toxicological results in cases with different causes of deaths. Concentrations of the enantiomers of VEN and metabolites were determined in femoral blood obtained from 56 autopsy cases with different causes of death. The drug analysis was done by liquid chromatography tandem mass spectrometry (LC/MS/MS) and the CYP2D6 genotyping by PCR and pyrosequencing. The mean (median) enantiomeric S/R ratios of VEN, ODV, NDV and DDV were 0.99 (0.91), 2.17 (0.93), 0.92 (0.86) and 1.08 (1.03), respectively. However, a substantial variation in the relationship between the S- and R-enantiomers of VEN and metabolites was evident (S/R ratios ranging from 0.23 to 17.6). In six cases, a low S/R VEN ratio (mean 0.5) was associated with a high S/R ODV ratio (mean 11.9). Genotyping showed that these individuals carried two inactive CYP2D6 genes indicating a poor metabolizer phenotype. From these data we conclude that enantioselective analysis of VEN and ODV can predict if a person is a poor metabolizer genotype/phenotype for CYP2D6. Knowledge of the relationship between the S- and R-enantiomers of this antidepressant drug and its active metabolite is also important since the enantiomers display different pharmacodynamic profiles.
    Forensic science international 08/2011; 214(1-3):124-34. DOI:10.1016/j.forsciint.2011.07.034 · 2.14 Impact Factor
    • "medications are still routinely used today to treat depression, but in many patients they have no or only limited efficacy [22]. SSRIs are associated with a number of side effects that can significantly impair quality of life (e.g., sexual dysfunction, weight gain, and emotional detachment) [23] and may increase the risk for suicide [24] [25]. Further, in a double-blind, placebo-controlled study, paroxetine (e.g., an SSRI antidepressant) failed to alleviate the vegetative symptoms of depression, such as fatigue and anorexia [26], illustrating the frequent problem of residual depressive symptoms during antidepressant treatment and supporting the hypothesis that the pathogenesis of major depressive disorder involves multiple neurocircuits and neurochemicals. "
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    ABSTRACT: By the year 2020, depression will be the 2nd most common health problem in the world. Current medications to treat depression are effective in less than 50% of patients. There is the need for novel treatments for depression to address the high rates of resistance to current treatment and the chronic residual symptoms in many patients treated for depression. The heterogeneity of major depressive disorder suggests that multiple neurocircuits and neurochemicals are involved in its pathogenesis thus, finding an alternative to neurotransmitter agonist- or antagonist-based treatments offers an important new approach. Cellular therapy is an emerging treatment strategy for multiple diseases, including depression. Based upon their in vivo function as "nurse cells" within the testis and the documented viability, efficacy, and safety of Sertoli cells transplanted into multiple tissues, including brain, the potential for these cells to provide a neuroprotective, anti-inflammatory, and trophic environment for neurons should be considered. It is proposed that the combination of self-protective, immunoregulatory and trophic properties of Sertoli cells may confer a unique potential for depression treatment and avoid many of the risks and challenges associated with stem cell therapies. At the very least, studies of the effects of Sertoli cell transplantation will add substantially to our understanding of the cellular and molecular processes that underlie depression.
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