BioEd Online

With the suggested link between selective serotonin-reuptake inhibitors (SSRIs) and suicidal behaviour in children generating ongoing and heated debate, one thing is clear: the nature and treatment of depression remains an area of great mystery.

Although SSRIs have provided much-needed relief for many children diagnosed with depression, for others it has brought nothing but heartbreak, with evidence indicating that SSRIs can make some patients agitated, violent and suicidal. The problem is that researchers and doctors can't distinguish between those who will respond favourably to SSRIs and those who will respond poorly.

One unsolved issue is whether the action of antidepressants differs between children and adults. Treating children as smaller versions of adults is common medical practice, but depression in children could be different, as the brain is rapidly developing into the late teens.

"There is surprisingly little research, clinical or experimental, done on this issue," says Eero Castren, Sigrid Jusélius Professor of Neuroscience at the University of Helsinki, Finland. "The current assumption seems to be that there are no fundamental differences and the only thing that you need to worry about is the appropriate dose."

Even if such differences were identified, the story wouldn't end there. "The question which next arises is who is a child and who is adult, and where is the line," says Castren. "These are some of the difficult questions that adolescent psychiatrists face when trying to help their suffering young patients."

More than 90% of people who attempt suicide or suicide victims have a diagnosable psychiatric illness, most commonly a mood disorder. The goal of understanding what triggers suicidal behaviour is not immediately in sight, but researchers are beginning to unravel important neurobiological mechanisms that could predict who would be prone to such impulses.

The most widely accepted model for suicidal behaviour is the stress-diathesis model proposed by John Mann, Professor of Psychiatry and Radiology at the New York State Psychiatric Institute, United States¹. Stress acts as an environmental 'straw that breaks the camel's back', such as acute worsening of a psychiatric disorder, that sets off a predisposition to suicidal behaviour, known as a diathesis.

This predisposition includes a combination of factors such as childhood experiences and familial or genetic factors. Most neurochemical evidence indicates that at least part of the diathesis response in depressed patients and suicide victims involves a deficiency in the neurotransmitter serotonin in a region of the brain involved in executive function (which includes how we act on impulse), called the ventral prefrontal cortex.

But SSRIs work by keeping serotonin in the synapses between neurons for longer than normal so that it can continue its effect, which in fact might explain how they can help.

"[SSRIs] enhance serotonin function to a progressively greater degree over several weeks according to animal studies and this lag in efficacy may leave patients vulnerable to acting on their suicidal feelings," says Mann. "It does not mean the drugs are responsible."

Mann says that a lack of rapid improvement in symptoms and the side effects of medication can lead to disappointment, especially because depressed patients are so pessimistic to begin with. Next-generation treatments that aim to reduce this lag by acting more quickly are currently under development.

Other neurobiological differences between adult and adolescent suicide could provide more telltale signs.

For example, a group led by Ghanshyam Pandey, Professor of Pharmacology in Psychiatry at the University of Illinois at Chicago, has found that there are differences in levels of guanine-nucleotide-binding proteins (G proteins) between adults and teenage suicides². Around 80% of receptors for neurotransmitters, including serotonin, hormones and neuromodulators elicit their responses through G proteins.

"The major question of whether these differences in the neurobiological abnormalities between adult and adolescent suicide explain the SSRI-induced suicidality is not clear and that will need to be addressed only after further work with SSRIs," says Pandey.

The fact that suicidal behaviour is in part heritable has led researchers to hunt for a predisposing gene or genes. These efforts have met with mixed success, but earlier this year, researchers identified six chromosomal regions that seem to harbour genes influencing suicidal behaviour in families with depresssion³.

"Interestingly, some suicide risk loci appear to influence the development of suicidal behaviours in patients with one psychiatric disorder, or diagnostic subtype, but not another," says George Zubenko, Professor of Psychiatry at the University of Pittsburgh School of Medicine, and lead researcher of this study.

Zubenko hopes to track down the specific genes in the identified linkage regions that influence the risk of depressive disorders and suicide. But in the shorter-term, he says these studies could help to identify high-risk individuals, for whom early intervention may save lives, and help optimise existing treatment administration. "The current rate limiting step is raising the funds to support these initiatives," says Zubenko.