Suicidality and aggression during antidepressant treatment: systematic review and meta-analyses based on clinical study reports
BMJ 2016; 352 doi: https://doi.org/10.1136/bmj.i65 (Published 27 January 2016) Cite this as: BMJ 2016;352:i65
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The authors ofthis paper essentially duplicate, with more limited data, many of the analyses presented in our 2009 BMJ paper but appear not to have read our paper very carefully. They write, "The FDA did not consider the limitations of the trials that we identified and introduced some of their own—for example, by only counting events within 24 hours after the randomised phase was over." Our event counts were based upon individual adverse event reports because we were concerned that the assessments by pharmaceutical sponsors may not have been accurate. Unlike the authors, we used a validate and standardized instrument to determine suicidal ideation or behavior; their determinations appear to have been more subjective. As for the 24 hour "limitation", this referred to the time of initial suicidal ideation or behavior; a subject who attempted suicide but whodid not die from the attempt until several days later would have been counted - not much of a limitation.
As for their statement that "an FDA employee published a paper in 2001 using FDA data that showed 22 suicides in 22 062 patients randomised to antidepressants,35 which equates to 10 per 10 000 population, but in the large FDA meta-analysis five years later, five suicides were reported in 52 960 patients, or 1 per 10 000 population," the "FDA employee" in question is the second author of our paper. The count of 22 suicides refers to all suicides in both placebo and treated groups and during open-label extensions and studies. The count of 5 suicides refers to antidedepressant-treated subjects only during double-blind treatment periods.
Competing interests: No competing interests
The concept that mental illnesses 'require chemical treatment' is undermined, rather than supported by this research. The data shows that the chemical treatment increases suicidality and aggression, relative to placebo. Thus, chemical treatment is contra-indicated.
In stark contrast, there are no negative side-effects from bona-fide psychotherapies, such as interpersonal therapy, CBT, or other forms. Psychotherapy should be considered a first line of intervention, especially for children, adolescents, and young adults.
A second line of argument against chemical treatment is that the research is clear that the major cause of most mental health problems is psychological injury, such as abuse in childhood. There is no solid data that depressed people have a chemical imbalance that needs medications, but there is robust research that they have psychological injuries. And where there is psychological injury, then psychotherapy should be the preferred intervention to heal it.
References
http://www.ncbi.nlm.nih.gov/pubmed/24756625
http://www.ncbi.nlm.nih.gov/pubmed/16999880
Competing interests: No competing interests
In my opinion the assessment and treatment of “depression” with anti-depressant drugs needs skilled care and an empathic stable therapeutic relationship.
Care for such patients can be very challenging. Sometimes desperate unhappy depressed people, who find no comfort from antidepressants, and who become alienated from their friends, family or therapists, can see no option but to kill themselves; sometimes the agitating effect of some of these drugs (especially if mixed with alcohol) provokes impulsive self destruction; sometimes a phase of the recovery from very serious psychomotor retardation is increased activity before relief of depression (and then suicide) and sometimes a switch into a mixed state or mania provokes very risky behaviour.
Treatment of people with antidepressants is a tricky business and those treated with these drugs need weekly (or twice weekly or even daily) monitoring by an experienced clinician or even inpatient care. In my opinion nobody should prescribe these drugs without organising such care (or doing it themselves). However all to often the response is “come back and see me if things don’t get better” or referral for continuous reassessment by a succession of strangers from a “home treatment team”.
Treatment with antidepressants is a reason for good quality consistent patient contact, and is not an alternative to it.
Competing interests: No competing interests
The missing piece here is that the cookie-cutter diagnosis of depression now practiced with our high volume, low pay, fee for service system often misses bipolar spectrum disorders. Unipolar depression was known as a disease of middle age so that there would be an over-representation of bipolarity amongst youth showing up in the system with depressive symptoms. Bipolar illness is known to produce a switch to hypomania in response to anti-depressants, leading to impulsivity/irritability and increased suicide risk.
Furthermore our cookie-cutter system also no longer has time or room to really just sit with people and help them to adjust to and make meaning with respect to having a "mental illness" requiring chemical treatment. The diagnosis and prescription is likely to make them feel even more alienated and alone, a piece even more critical amongst youth struggling to find their place and self-concept. Again this will be more an issue with younger people who will not have already dealt with adjusting to such a diagnosis earlier in life. Our over-application of the industrial approach to everything including with respect to ourselves and each other, is in the final throes of failure.
Competing interests: No competing interests
With depression already linked to intimate partner violence, impulsive driving, severe traumas due to risky behavior, binge drinking, dangerous sexual conduct, [2][3][5] even slight escalations in aggression, during pharmacological treatment, can indirectly increase mortality.
Resulting alcohol abuse is in itself linked to suicidality and aggression. [1][4]
Such deduced rises in morbidity and mortality, of patients sexual partners children pedestrians and innocent bystanders, are never going to be registered in anonymized patient data of clinical drug reports or pharmaceutical company websites.
Clinicians must still bear in mind this undocumented mortality, though, before deciding to administer antidepressant pills.
References
[1] aggression linked to alcohol abuse
http://www.ncbi.nlm.nih.gov/pubmed/24997103
[2] binge drinking linked to depression
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2909755/
http://www.ncbi.nlm.nih.gov/pubmed/26444863
http://www.ncbi.nlm.nih.gov/pubmed/26235432
http://www.ncbi.nlm.nih.gov/pubmed/26051511
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3775848/
[3] traumas and risky behaviours linked to depression
http://www.ncbi.nlm.nih.gov/pubmed/26561275
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3775848/
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3771635/
[4] binge drinking linked to suicidality
http://www.ncbi.nlm.nih.gov/pubmed/16445162
[5] impulsive-aggressive driving linked to depression
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4540139/
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4536837/
Competing interests: No competing interests
Suicidality and aggression during antidepressant treatment: systematic review and meta-analyses based on clinical study reports
The review and meta-analysis of Sharma et al. demonstrate the complex problems of clinical trials, unpublished studies and of a meta- analysis, especially. Caution is definitely required in interpreting the results given the methodological limitations of all included trials in terms of internal and external validity. Size and clinical meaningfulness of statistically significant results are uncertain. The meta-analysis of Kirsch et al. [1] attracted great attention. The authors reported about only modest benefits over placebo treatment and the relevance of unpublished trial data. Drug-placebo differences in antidepressant efficacy would be relatively small even for severely depressed patients. Möller H. [2] argued that “results of metaanalyses should not too naively be interpreted as the 'truth' as regards to the evidence based psychopharmacotherapy”.
Furthermore the association between use of antidepressants and incidence of suicide has yielded inconsistent results and is subject of considerable controversy. Because of the incongruity between the wide use of and the weak evidence base for the efficacy and safety of antidepressants, studies with a new design, long- term trials and post marketing surveillance investigations are necessary. Gusmão R [3] investigated suicide rates between 1980 and 2009 in European countries. Suicide rates tended to decrease more where there has been a greater increase in the use of antidepressant drugs. An European drug surveillance program (“Arzneimittelsicherheit in der Psychiatrie”) [4] was performed in 85 psychiatric hospitals from 1993 until 2008. A total of 142.090 adult patients taking antidepressant medication, were observed. 33 incidents of suicidality (12 cases of suicidal ideation, 18 attempts, and 3 completed suicides) were documented. 23 cases were associated with restlessness, 9 with impulsiveness. A higher incidence of suicidality was observed for selective serotonin reuptake inhibitors (0.034%; 95% CI, 0.020-0.054) and serotonin-norepinephrine reuptake inhibitors (0.034%; 95% CI, 0.015-0.068) compared to tricyclic antidepressants (0.002%; 95% CI, 0.000-0.014). Clinicians need to keep in mind that suicidality has a high incidence in depressive disorders. But there is possible evidence that antidepressant medication can trigger suicidality. It is time for a balanced view of the individual risk-benefit ratio under the aspects of risk factors of patients, for example age [5], previous suicide attempts or comorbidity and antidepressant treatment (after starting the medication, increase of dosage or co medication), respectively.
1) Kirsch I et al. Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration. PLoS Med 2008; 5(2):e45 2) Möller HJ Isn't the efficacy of antidepressants clinically relevant? A critical comment on the results of the metaanalysis by Kirsch et al. 2008 Eur Arch Psychiatry Clin Neurosci. 2008 ;258(8):451-5 3)Gusmão R et al. Antidepressant Utilization and Suicide in Europe: An Ecological Multi-National Study. PLoS One. 2013 19;8(6):e66455. 4) Stübner S et al. Suicidality as rare adverse event of antidepressant medication: a report from the AMSP multicenter drug safety surveillance project.J Clin Psychiatry 2010; 71(10):1293-307 5)Stone M et al. Risk of suicidality in clinical trials of antidepressants in adults: analysis of proprietary data submitted to US Food and Drug Administration. BMJ 2009; 339:b2880
Competing interests: No competing interests