SSRIs and Suicidal Ideation: Is There A Genetic Link?

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ResearchBlogging.org

Despite what the news might have you believe, it is quite rare for a depressed person to exhibit increased suicidal thinking after they have begun treatment with an SSRI, such as citalopram (celexa). According to the statistics, so-called "treatment-emergent suicidal ideation" occurs only in approximately 4% of all people taking citalopram, whereas this same phenomenon also occurs in 2% of all placebo-treated cases. However, in those unusual cases where suicidal ideation does occur as a result of treatment with an SSRI, it can cause a great deal of distress for the people experiencing it, and for their families and close friends. Initially, this phenomenon was thought to only occur in teenagers, but later, it was found to occur at similar rates in the general population, regardless of age. As a result, the FDA-mandated a black box warning that highlighted the potential for suicidal ideation in youths, but this warning was later expanded to include adults.

During a series of studies in youths into this phenomenon, it was found that the biggest risk for increased suicidal ideation occurs within a few weeks of initiating treatment with citalopram, or after a dosage adjustment. However, fortunately, none of the study subjects actually completed suicide despite increased suicidal ideation.

But to gain a clearer understanding of the potential genetics underlying treatment-emergent suicidal ideation, a study was designed for adult volunteers throughout the USA who were suffering major depression. The purpose of this study was to initiate and document treatment of volunteers with citalopram and to collect and screen volunteer DNA for the identification of genetic markers that might be associated with treatment-emergent suicidal ideation.

After analyzing 68 genes, the authors identified several genetic markers, GRIA3 and GRIK2, that were associated with treatment-emergent suicidal ideation, and further, they found that both these markers and treatment-emergent suicidal ideation occurred in a dose-dependent manner. Interestingly, these genetic markers were associated with the glutamate receptor pathway, which is consistent with previous data suggesting that antidepressants affect glutamate signaling. Glutamate receptors form pores through a cell membrane that, when they open, allow excitatory messages to be passed from one nerve cell and another.

Also, and of clinical importance, those people who developed treatment-emergent suicidal ideation also were less likely to respond well to citalopram treatment and thus, their treatment paradigms were changed after 14 weeks.

Volunteers with the GRIA3 variant showed nearly a doubled risk of developing suicidal thoughts, while volunteers with the GRIK2 variant showed an eightfold increase in risk. Those study volunteers that had both markers -- an extremely rare phenomenon -- showed a 15-fold increase in risk.

"The findings suggest part of the tendency to develop this type of reaction to antidepressants might be genetically determined, and this might be used in the future to develop genetic screening tests to identify people who might be at risk," says Francis McMahon of the National Institute of Mental Health (NIMH) in Bethesda, Maryland. McMahon led the study.

So does this mean that there will be a test that can predict if a person will react to treatment with a particular SSRI? Perhaps there will be in the future. However, even though the results of this study are promising, these data should be viewed as preliminary only, until further studies can be carried out to replicate the results and also to identify which gene variants are associated with the genetic markers identified by this study. Additionally, it is always important to realize that genetic analyses are no substitute for supportive medical care: people suffering from major depression should be carefully monitored by their family, friends and doctors even after they begin taking antidepressants, and whenever their antidepressant dosage is adjusted.

"They are leading the field into the potential for tailoring treatments to individual gene differences and new general targets for the treatment of depression," observed Elliot Gershon, a psychiatric genetics researcher at the University of Chicago in Illinois, who wrote a companion editorial to the study.

Source

"Genetic Markers of Suicidal Ideation Emerging During Citalopram Treatment of Major Depression" by Gonzalo Laje, Silvia Paddock, Husseini Manji, A. John Rush, Alexander F. Wilson, Dennis Charney and Francis J. McMahon. Am J Psychiatry 164:1530-1538 (October 2007).

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I have been on SRIs for a while now along with other meds to control Bipolarisim.

When I first started SRI treatment, I went through a couple of very rough weeks were Self Destruction was a common and reoccurring theme of my thoughts.

I worked through it while the meds reached therapeutic levels and within 5-6 weeks my Self Destructive thoughts were less and less common and finally stopped all together.

Was I predesposed to these thoughts or were they the product of uncontrolled Manic Depression?

I'm still pondering that one.

Dave Dragon
Ride it like you stole it

My experience was in the opposite direction. I had depression and rather severe suicidal ideation, and the SNRI Cymbalta rapidly evened things out. Just goes to show that the effects are variable.

By natural cynic (not verified) on 03 Oct 2007 #permalink

"So does this mean that there will be a test that can predict if a person will react to treatment with a particular SSRI? Perhaps there will be in the future. "

acutally, there is already a company selling a test based on this study.

By sciencewriter (not verified) on 03 Oct 2007 #permalink

Yet again, Bah!

Well over ten years ago on Walkers In Darkness, we'd figured out that risk of suicide peaked when starting anti-depressant treatment -- because your energy comes back before your moods normalize. (That is, someone who's paralyzed by depression may well be too lethargic/hopeless to actually make an attempt.)

As far as I'm concerned, the whole "ADs cause suicide" business is just another hatchet job -- the real problem is doctors who can't be bothered (or aren't allowed by insurance companies) to properly monitor their patients.

By David Harmon (not verified) on 04 Oct 2007 #permalink

Does a family history of alcohol dependency, violence, and early death from same, give us a hint as to our predilection ? All my paternal family died of Alcohol before fifty, with the exception of my father. Murder if spouses made divorce e a moot point
Leaving the Irish and Welsh, the maternal French/German seems quiet until you find
Mama's sister drank two cans of draino. that's despair. The cousin hung himself in a garden, when the neighbors founmnd out he was gay.
Can report the generation following was mostly 'balanced', with advanced degrees. Nost of that group at least survived till fifty.
Of course can report the NEXT group is already making up for lost time.
Famlies need a reunion to let folks know what's up...gene wise!

By judyroth@mac.com (not verified) on 04 Oct 2007 #permalink

Current Depression Medications: Do The Benefits Outweigh the Harm?

Presently, for the treatment of depression and other what some claim are mental disorders, as they are questionable, selective serotonin reuptake inhibitors are the drugs of choice by most prescribers. Such meds, meds that affect the mind, are called psychotropic medications. SSRIs also include a few meds in this class with the addition of a norepinephrine uptake inhibitor added to the SSRI, and these are referred to SNRI medications. Examples of SNRIs are Cymbalta and Effexor. Some consider these classes of meds a next generation after benzodiazepines, as there are similarities regarding their intake by others, yet the mechanisms of action are clearly different, but not their continued use and popularity by others.
Some Definitions:
Serotonin is a neurotransmitter thought to be associated with mood. The hypothesis was first suggested in the mid 1960s that this neurotransmitter may play a role in moods and emotions in humans. Yet to this day, the serotonin correlation with such behavioral and mental conditions is only theoretical. In fact, the psychiatrist's bible, which is the DSM, states that the definite etiology of depression remains a mystery and is unknown. So a chemical imbalance in the brain is not proven to be the cause of mood disorders, it is only suspected with limited scientific evidence. In fact, diagnosing diseases such as depression is based on subjective assessment only, as interpreted by the prescriber, so one could question the accuracy of such diagnoses.
Norepinephrine is a stress hormone, which many believe help those who have such mood disorders as depression. Basically, with the theory that by adding this hormone, the SSRI will be more efficacious for a patient prescribed such a med.
And depression is only one of those mood disorders that may exist, yet possibly the most devastating one. An accurate diagnosis of these mood conditions lack complete accuracy, as they can only be defined conceptually, so the diagnosis is dependent on subjective criteria, such as questionnaires. A social patient history is uncertain and tricky. There is no objective diagnostic testing for depression. Yet the diagnosis of depression in patients has increased quite a bit over the decades. Also, few would argue that depression does not exist in other people. Yet, one may contemplate, actually how many other people are really depressed? What is believed is that if one is disabled or impaired from a mental paradigm, treatment is necessary and appropriate.
Several decades ago, less than 1 percent of the U.S. populations were thought to have depression. Today, it is believed that about 10 percent of the populations have depression at some time in their lives. Why this great increase in the growth of this condition remains unknown and is subject to speculation. What is known is that the psychiatry specialty is the one specialty most paid to by certain pharmaceutical companies for ultimately and eventual support of their psychotropic meds, as this industry clearly desires market growth of these products. Regardless, SSRIs and SRNIs are the preferred treatment methods if depression or other mood disorders are suspected by a health care provider. Yet these meds discussed clearly are not the only treatments, medicinally or otherwise, for depression and other related disease states.
Over 30 million scripts of these types of meds are written annually, and the franchise is around 20 billion dollars a year, with some of the meds costing over 3 dollars per tablet. There are about ten different SSRI/SRNI meds available, many of which are now generic, yet essentially, they appear to be similar in regards to their efficacy and adverse events. The newest one, a SNRI called Pristiq, was approved in 2008, and is believed to being promoted for treatment for menopause. The first one of these SSRI meds was Prozac, which was available in 1988, and the drug was greatly praised for its ability to transform the lives of those who consumed this medication in the years that followed. Some termed Prozac, 'the happy pill'. In addition, as the years went by and more drugs in this class became available, Prozac was the one of preference for many doctors for children. A favorable book was published specifically regarding this medication soon after it became so popular with others.
Furthermore, these meds have received additional indications besides depression for some really questionable conditions, such as social phobia and premenstrual syndrome. With the latter, I find it hard to believe that a natural female experience can be considered a treatable disease. Social phobia is a personality trait, in my opinion, which has been called shyness or perhaps a term coined by Dr. Carl Jung, which is introversion, so this probably should not be labeled a treatable disease as well. There are other indications for certain behavioral manifestations as well with the different SSRIs or SRNIs. So the market continues to grow with these meds. Yet, it is believed that these meds are effective in only about half of those who take them, so they are not going to be beneficial for those suspected of having certain medical illnesses treated by such meds. The makers of such meds seemed to have created such conditions besides depression for additional utilization of these types of medications, and are active and have been active in forming symbiotic relationships with related disease- specific support groups, such as providing financial support for screenings for the indicated conditions of their meds- screening of children and adolescents in particular, I understand, and as a layperson, I consider such activities dangerous and inappropriate for several reasons.
Danger and concerns by others primarily involves the adverse effects associated with these types of meds, which include suicidal thoughts and actions, violence, including acts of homicide, and aggression, among others, and the makers of such drugs are suspected to have known about these effects and did not share them with the public in a timely and critical manner. While most SSRIs and SNRIs are approved for use in adults only, prescribing these meds to children and adolescents has drawn the most attention and debate with others, such as those in the medical profession as well as citizen watchdog groups. The reasons for this attention are due to the potential off-label use of these meds in this population, yet what may be most shocking is the fact that some of the makers of these meds did not release clinical study information about the risks of suicide as well as the other adverse events related to such populations, including the decreased efficacy of SSRIs in general, which is believed to be less than 10 percent more effective than a placebo. Paxil caught the attention of the government regarding this issue of data suppression some time ago, this hiding such important information- Elliot Spitzer specifically, as I recall.
And there are very serious questions about the use of SSRIs in children and adolescents regarding the effects of these meds on them. For example, do the SSRIs correct or create brain states considered not within normal limits, which in effect could cause harm rather than benefit? Are adolescents really depressed, or just experiencing what was once considered normal teenage angst? Do SSRIs have an effect on the brain development and their identity of such young people? Do adolescents in particular become dangerous or bizarre due to SSRIs interfering with the myelination occurring in their still developing brains? No one seems to know the correct answer to such questions, yet the danger associated with the use of SSRIs does in fact exist. It is observed in some who take such meds, but not all who take these meds. Yet health care providers possibly should be much more aware of these possibilities
Finally, if SSRIs are discontinued, immediately in particular instead of a gradual discontinuation, withdrawals are believed to be quite brutal, and may be a catalyst for suicide in itself, as not only are these meds habit forming, but discontinuing these meds, I understand, leaves the brain in a state of neurochemical instability, as the neurons are recalibrating upon discontinuation of the SSRI that altered the brain of the consumer of this type of med. This occurs to some degree with any psychotropic med, yet the withdrawals can reach a state of danger for the victim in some classes of meds such as SSRIs, it is believed.
SSRIs and SRNIs have been claimed by doctors and patients to be extremely beneficial for the patient's well -being regarding the patient's mental issues where these types of meds are used, yet the risk factors associated with this class of medications may outweigh any perceived benefit for the patient taking such a drug. Considering the lack of efficacy that has been demonstrated objectively, along with the deadly adverse events with these meds only recently brought to the attention of others, other treatment options should probably be considered, but that is up to the discretion of the prescriber. It is my hope that such a prescriber rules out possible deficiencies of a patient they diagnose as being mentally impaired, such as other diseases or meds that could cause a mental illness, imbalances with the patient's harmones, deprivation of light and/or sleep, or life stressors. Rarely do prescribers consider such possibilities.

"I use to care, but now I take a pill for that." --- Author unknown

Dan Abshear