In recent years there has been considerable concern that certain classes of drugs, for example antidepressants, may increase the risk of suicide. In this current opinion article, we examine the literature on methodological and statistical approaches to the design and analysis of suicidal event studies. Experimental, ecological and observational studies of the relationship between drugs and suicidal events (thoughts, attempts and completion) are discussed. Areas considered include analysis of spontaneous reporting system data, ecological trends in national and/or small area (e.g. county) suicide rates, meta-analyses of randomized clinical trials, and large-scale medical claims data. New statistical and experimental strategies for investigating possible associations between drugs and suicide are highlighted, and we suggest directions for future statistical/methodological research. To put this into context, we then review the most recent literature on the relationship between drugs (antidepressants, antiepileptics, varenicline, montelukast and antipsychotics) and suicidal events. Overall, there appears to be little evidence that drugs increase the risk of suicide and related behaviour. Numerous lines of evidence in adults clearly demonstrate that inadequate treatment of depression (pharmacotherapy and/or psychotherapy) is associated with increased risk of suicidal behaviour. In children, the results are less clear and further study is required to better delineate which children benefit from treatment and who may be at increased risk as a consequence of treatment. From a statistical and methodological perspective, the field of pharmacoepidemiology is a fertile area for statistical research, both in theory and in application. In general, methods have been adopted from other areas such as general epidemiology, despite the singular nature of many of the problems that are unique to drug safety in general, in particular the study of rare events. Finally, there is considerable debate concerning the communication of risk. For suicide, regulatory action has been taken largely on the basis of evidence suggesting increased risk of suicidal thoughts. However, suicidal thoughts are quite common, particularly among patients with depression, and may have little relationship to suicidal behaviour and/or completion.
"Although efavirenz has been associated with spontaneous reports of psychiatric ADRs, there was no clear evidence from a systematic review that patients taking efavirenz were at increased risk of suicide . A recent review found little evidence for an increased risk of suicide and suicidal behaviour with antidepressants, antiepileptics, varenicline, montelukast and antipsychotics . It is reassuring that, with the exception of SSRIs in young people, other study designs have not confirmed elevated risks of neuropsychiatric adverse effects for medicines with high numbers of spontaneous reports in our study. "
[Show abstract][Hide abstract] ABSTRACT: Background
Psychiatric adverse drug reactions (ADRs) are distressing for patients and have important public health implications. We identified the drugs with the most frequent spontaneous reports of depression, and fatal and non-fatal suicidal behaviour to the UK’s Yellow Card Scheme from 1998 to 2011.
We obtained Yellow Card data from the Medicines and Healthcare products Regulatory Agency for the drugs with the most frequent spontaneous reports of depression and suicidal behaviour from 1964 onwards. Prescribing data were obtained from the NHS Information Centre and the Department of Health. We examined the frequency of reports for drugs and estimated rates of reporting of psychiatric ADRs using prescribing data as proxy denominators from 1998 to 2011, as prescribing data were not available prior to 1998.
There were 110 different drugs with ≥ 20 reports of depression, 58 with ≥10 reports of non-fatal suicidal behaviour and 33 with ≥5 reports of fatal suicidal behaviour in the time period. The top five drugs with the most frequent reports of depression were the smoking cessation medicines varenicline and bupropion, followed by paroxetine (a selective serotonin reuptake inhibitor), isotretinoin (used in acne treatment) and rimonabant (a weight loss drug). Selective serotonin reuptake inhibitors, varenicline and the antipsychotic medicine clozapine were included in the top five medicines with the most frequent reports of fatal and non-fatal suicidal behaviour. Medicines with the highest reliably measured reporting rates of psychiatric ADRs per million prescriptions dispensed in the community included rimonabant, isotretinoin, mefloquine (an antimalarial), varenicline and bupropion. Robust denominators for community prescribing were not available for two drugs with five or more suicide reports, efavirenz (an antiretroviral medicine) and clozapine.
Depression and suicide-related ADRs are reported for many nervous system and non-nervous system drugs. As spontaneous reports cannot be used to determine causality between the drug and the ADR, psychiatric ADRs which can cause significant public alarm should be specifically assessed and reported in all randomised controlled trials.
[Show abstract][Hide abstract] ABSTRACT: In the last 10 years, numerous experimental studies have revealed the participation of the endocannabinoid system in the control of emotional behavior and mood through the activation of the CB1 cannabinoid receptors. Endocannabinoids are able to exert a regulative control of different physiological mechanisms that are impaired during mood disorders, including monoaminergic system, the activity of pituitary-adrenal axis, the release and activation of neurotrophic factors that promotes neuroplasticity and adapted behavior, and probably neuroinflammatory cytokines release during the depressive disorders. Considering the body of elements that acts under the control of the endocannabinoid system and the key role played by the activation of the CB1 cannabinoid receptors in the control of emotion and mood, we had proposed that genetically modified mice lacking the CB1 cannabinoid receptors could represent a genetic model for depression. These animals generated by three distinct laboratories behave normally under basal conditions, but they could display an altered behavior under adverse environmental conditions. In this review, we have integrated most of the study that have been developed using mice lacking CB1 cannabinoid receptor for the studies of emotional responses. We have focused our attention not only in the data obtained using different behavioral paradigms, but also in different biomarkers that have been classically or recently associated to mood disorders, such as the deregulation of the serotonergic system, the reported impairment in neurotrophic factors and plasticity function described for depression, the alterations in the pituitary-adrenal axis function, and the lately reported role for inflammatory factors in the mood regulation. Finally, clinical studies support and confirm the obtained findings in animal models and lead us to propose that mice lacking CB1 cannabinoid receptor could represent a validate and appropriate model to evaluate depressive-like disorders in animals.
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