16.01.2004

From Depression to Suicide? Health officials in several countries, including Germany, the UK, and elsewhere have recently issued warnings concerning a potential suicide risk when patients, especially younger people, take SSRI-type antidepressants (AD). The so-called selective serotonin re-uptake inhibitors (= SSRI) which increase the availability of the neurotransmitter serotonin in nerve endings, especially of the brain, have been the latest class of antidepressant drugs along with the older tricyclic antidepressants (TCA), monoaminooxidase (MAO) inhibitors and lithium salts. Hardly surprising, their momentum in drug market has increased tremendously due to a more favorable profile of therapeutic and adverse drug effects, but also increased has concern about drug-related suicidality with SSRI. The table shows a list of SSRI that are currently approved in Germany, along with its year of approval and some brand names. Approved selective serotonin re-uptake inhibitors (SSRI) YoA* Active substance German brand names Other brand names 1996 Citalopram Cipramil®, Sepram® Celexa®, Seropram® 1994 Fluoxetine Fluctin® Mutan®, Prozac® 1996 Fluvoxamine Fevarin® Luvox® 1994 Paroxetine Seroxat®, Tagonis® Paxil® 1996 Sertraline Gladem®, Zoloft® Lustral® 1996 Trazodone** Thombran® Dividose®, Trittico® 1996 Venlafaxine*** Trevilor® Effexor® * YoA = Year of earliest approval (in Germany) ** in animal studies at low doses (<1mg/kg) also acts as a serotonin receptor antagonist *** also acts as a (selective) norepinephrine re-uptake inhibitor (SNRI) Before looking into the SSRI-related suicide problem it should be noted that this risk has always accompanied the use of AD drugs. It is hypothesized that after onset of antidepressive therapy the switch from lethargy to activity may be precede the lightening of mood under yet unknown circumstances, so that "negative thoughts" and "poorly controlled drive" coincide with a bad outcome. Interesting to note that reports of SSRI-associated suicide have been around since the earliest clinical trials with SSRI. But what's different with the SSRI? To put things into perspective, here are some provocative statistical figures re "Antidepressants & Suicide", presented by Dr Khan of the Northwest Clinical Research Center (Bellevue, WA) taken from the Web. Completed suicides in the US 1985-2000* Drug therapy Suicides per 100,000 patients <none> (average population) 11 olanzapine, quetiapine, risperidone (atypical antipsychotics) 752 citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline (SSRI) 718 bupropion, nefazadone, mirtazapine (anxiolytics) 425 alprazolam (benzodiazepine tranquillizer) 136 valproate (anticonvulsant) 105 * out of a total number of 71,604 patients who attempted or committed suicide in clinical trials, as reported to the FDA. The figures may seem astounding, but before conclusions are drawn, a closer look is appropriate. Here are some key questions that need to be addressed BEFORE judging the figures in terms of drug-related or - dare I say - drug-induced suicide risk: How many depressive patients would attempt or complete suicide without drug therapy? Did the suicides occur during active therapy, or was it a consequence of inappropriate drug withdrawal or non-compliance? Were the cases that had been selected for inclusion representative or "picked"? Has the medication been properly dosed with all necessary measures to counteract suicide attempts during the induction phase* and the wash-out period? * It is well known that after initiation of conventional AD therapy, adverse effects come first, followed by increased drive a/o agitation, and finally lightening of mood, a process that may require several weeks. Q1 has been addressed by Dr Khan on another occasion when he estimated that 1,750 suicide attempts/completions per 100,000 were noted in the placebo groups vs 710/100,000 in the verum groups of cited studies. Until we have more details and background about these questions, it remains difficult to tell if AD, especially SSRI, really increase suicide risk in depressive patients. It may also be worth to look into subsets of the above survey, namely young and geriatric patients, and to watch for co-morbidity and (hidden) self-medication. Such complementary surveys have now been initiated, and Dr Khan's group has recently published one entitled "Suicide risk not increased with SSRI antidepressants", stating that suicide attempts during SSRI treatment are no more likely than with any other class of AD. So turning back to our top question "What's different with the SSRI?", the answer may be simple: nothing. BUT perception of risk is likely to be increased due to the otherwise "innocent" drug profile of SSRI. Let's hope that physicians got the message and continue to be aware thereof before prescribing SSRI and other AD, especially to adolescent and geriatric patients. 11:57:23 PM