Efficacy and safety of SSRIs in the treatment of childhood depression

Background:

Just as our concepts of childhood have changed, so have our concepts of childhood problems. It was only in the late 1980s that our understanding of childhood depression began a far reaching transformation. Before this, childhood depression was viewed as very rare, different from adult depression, and not amenable to treatment with antidepressants. A shift in theory, and consequently practice, then took place as

Influential academics claimed that childhood depression was more common than previously thought (8-20% of children and adolescents), resembled adult depression, and was amenable to treatment with antidepressants (often resulting in antidepressants

Becoming a first line treatment). Childhood depression has become a popular

Notion, reflecting the broader cultural changes that have taken place in our view of childhood and its problems. "These days we are as likely to use medicalised terminology to describe children’s feelings (such as depressed) as we are less pathological descriptions (such as unhappy). Children with depressive disorders lack interest in activities they previously enjoyed, criticize themselves, and are pessimistic or hopeless about the future. They may feel sad or irritable. Problems at school arise from indecision and difficulties with concentration. Depressed children tend to lack energy and have problems sleeping. They may have stomach aches or headaches. Morbid thoughts may progress to suicidal thinking and even suicide attempts. For various reasons, some adults find it hard to accept that children may experience unpleasant psychological states such as depression."

Depression in children usually arises from a combination of genetic vulnerability, suboptimal early developmental experiences, and exposure to stresses. Compared with the literature on depression in adults, evidence from randomised controlled trials for the efficacy of treatments for depression in young people is scarce.

Antidepressants introduced since 1990, especially selective serotonin reuptake inhibitors and venlafaxine, have been used increasingly as first line treatment for depression in children.

The use of selective serotonin reuptake inhibitors (SSRIs) in children under 18 years old increased ten-fold (from 0.5 to 4.6 per 1000) in the UK from 1992 to 2001 (Murray et al, 2004). Usage rates are even higher in the USA, at 16.6 per 1000 (Delate et al, 2004), despite the existence of training and theoretical models for the treatment of mental disorders that are similar to those in the UK. Reasons for the increasing rates of use are likely to include heavy promotion of both medication and illness, distortion of the published data related to safety and efficacy, and underestimation by clinicians of the importance of the placebo response (Jureidini et al, 2004a).

Discussion:

There are several types of antidepressant medications used to treat depressive disorders. These include newer medications chiefly the selective serotonin reuptake inhibitors (SSRIs), the tricycles, and the monoamine oxidase inhibitors (MAOIs). The SSRIs and other newer medications that affect neurotransmitters such as dopamine or norepinephrine generally have fewer side effects than tricycles.

"Selective serotonin re-uptake inhibitors (SSRIs) are the name given to a group of antidepressant medicines. When used in reference to medicines, the term 'group' means that each of the drugs in the group is broadly similar to the others in the way that it works."(Wikipedia)
Differences between medicines within a group are usually fairly small, for example they may differ in dosage frequency or in their particular spectrum of side effects.

There are a number of SSRIs that are frequently used to treat depression. There is detailed information about these individual medicines in the fact sheets linked below:

How they work

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There are a number of SSRIs that are frequently used to treat depression. There is detailed information about these individual medicines in the fact sheets linked below:

How they work

In the , information is passed between two (nerve cells) via a , a small gap between the cells. The neuron that sends the information releases neurotransmitters (with serotonin among them) into that gap. The neurotransmitters are then recognized by on the surface of the recipient cell, which upon this stimulation, in turn, relays the signal. About 10% of the neurotransmitters are lost in this process; the other 90% are released from the receptors and taken up again by in the sending cell (thus reuptake).

has been linked to a lack of stimulation of the recipient neuron at a synapse. To stimulate the recipient cell, SSRIs inhibit the reuptake of serotonin. As a result, the serotonin stays in the synaptic gap longer than it normally would, and has the chance to be recognized again (and again) by the receptors of the recipient cell, which can finally be stimulated that way.

Why not give serotonin directly? First, serotonin ingested orally will not cross the , and therefore won't have an effect on brain functions. Second, pure serotonin would turn on every synapse it reaches, whereas SSRIs only enhance a signal that is already present, but too weak to come through.

SSRIs are described as 'selective' because they affect only the reuptake pumps responsible for serotonin, as opposed to earlier antidepressants, which affect other monoamine neurotransmitters as well. Because of this, SSRIs lack some of the side effects of the more general drugs.

is made from , an . If depression is caused by lack of serotonin, rather than insensitivity to it, SSRIs alone will not work well, whereas supplementing with tryptophan will.

Side effects

Suicidal behavior

A lot of publicity has been given to a few reports of people becoming suddenly suicidal while taking Prozac (fluoxetine) or Seroxat (paroxetine).As a result, this has been looked at very carefully in all the SSRIs by the Medicines and Healthcare Regulatory Authority (MHRA); the agency of the Department of Health that ensures medicines in the UK meet appropriate standards of safety, quality and effectiveness.
After studying all the available research, the MHRA decided in December 2003 that SSRIs (with the exception of fluoxetine) should not be prescribed for children under 18 because they may more do more harm than good in this age group.
In December 2004, the MHRA found that evidence linking SSRIs to suicidal behaviour in adults is weak and that the benefits of these medicines in adults generally outweigh any risks.

The SSRIs are proven to be very effective treatments for depression and most likely, it is the depressive illness itself that leads to suicidal feelings. However, as a precautionary measure, young adults over the age of 18 should be closely monitored when they start an SSRI, as suicidal behavior in general is more common in this age group than in older adults.

Neurotoxicity

Some studies suggested the possibility that SSRI`S may be neurotoxic.Neurotoxicity has been observed in cell lines. There have also been anecdotal reports of "mental fog" arising from SSRI use. Other studies have suggested that SSRI`s may increase the growth of new brains cells and that this may be responsible for their effects in depression. Also, SSRI`s may protect against neurotoxicity caused but other compounds as well as from depression itself.

Sexual side effects

It is well known that the selective serotonin reuptake inhibitors (SSRIs) can cause various types of sexual dysfunction such as anorgasmia, erectile dysfunction, and diminished libido. Initial studies found that such side effects occurs in less than 10%of patients ,but those studies relied on unprompted reporting ,so the frequency of such problems was underestimated. In more recent studies ,doctors have specifically asked about sexual difficulties ,and found that they are present in between 41%(Landen et al 2005)and 83% of patients (Hu et al 2004).This dysfunction occasionally disappears spontaneously without stopping the SSRI,and in most cases resolves after discontinuance .

Argument:

"A total of 477 patients in the six studies were treated with paroxetine, fluoxetine, sertraline, or venlafaxine ( 23% dropouts), and 464 were treated with placebo ( 25% dropouts). Of 42 reported measures, only 14 showed a statistical advantage for an antidepressant. None of the 10 measures relying on patient reported or parent reported outcomes showed significant advantage for an antidepressant, so that claims for effectiveness were based entirely on ratings by doctors. No study presented data on rates of attempted self harm, presentations to emergency or mental health services, or school attendance. "(BMJ, 2004)

Two small studies found no statistically significant advantage for antidepressants over placebo on any of the outcome measures reported. Of the remaining four papers, two did and two did not show statistically significant advantages for antidepressants over placebo on primary outcome measures.

"We meta-analysed the five published studies on selective serotonin reuptake inhibitors by using the standardised mean difference (Hedges' g) as the measure of effect. We averaged relevant outcome measures within studies and then pooled them across studies by using a random effects model. We included all continuous outcome measures related to depression and health related quality of life. The effect size was small 0.26 (95% confidence interval 0.13 to 0.40). Assuming a standard deviation of scores of 11 to 14 on the revised children's depression rating scale in depressed children, an effect size of 0.26 is equivalent to a very modest 3 to 4 point difference on the scale, which has a range of possible scores from 17 to 113. "(Edwards G, Anderson I, 1999)

"Because the follow up period for the randomised controlled trials was short, and numbers were relatively small, serious adverse effects were likely to be few. When they do occur, we would therefore expect authors to draw attention to them, along with data available from other sources that suggest that serious adverse effects might occur. Of 93 patients treated with paroxetine by Keller et al, 11 had serious adverse events, compared with 2/87 in the placebo group. The authors presented no statistical analysis, but the difference was significant (Pearson's 2 = 6.09, df = 1, P = 0.01). In spite of this striking difference in serious events between paroxetine and placebo, Keller et al concluded that, "paroxetine was generally well tolerated in this adolescent population, and most adverse effects were not serious," even though seven patients were admitted to hospital during treatment with paroxetine. Furthermore, despite five of these patients being admitted to hospital with events known to occur with the use of selective serotonin reuptake inhibitors, including suicidality, only one serious event (headache) was judged by the treating investigator to be related to paroxetine treatment. The criteria for determining causation of serious events were not stated."(BMJ, 2005)

Among 373 patients in the trial by Wagner et al, 9% (17/189) treated with sertraline withdrew because of adverse events, compared with 3% (5/184) in the placebo group. These authors also published no statistical analysis of this outcome or details of the adverse effects, but the difference in withdrawal rates was significant (Pearson's 2 = 6.62, df = 1, P = 0.01). Wagner et al reported seven adverse effects that occurred in at least 5% of the sertraline group, at least twice as often as in the placebo. Despite these results they concluded that, "sertraline is an effective, safe, and well tolerated short-term treatment for children and adolescents."

In response to concerns raised about suicidal behaviour and withdrawal effects, the UK Committee on Safety of Medicines (CSM) established an expert panel in 2002 to review paroxetine and other SSRIs. Access to all GlaxoSmithKline’s trials of paroxetine therapy revealed that the unpublished trials in children showed increased suicide risk and little evidence of efficacy. In fact, a GlaxoSmithKline internal memorandum showed that the company had known that their studies failed to demonstrate efficacy since at least 1998. After reconstitution because of potential conflicts of interest, the expert panel reported in December 2003, and the CSM declared all SSRIs, except fluoxetine, contraindicated for use in patients under 18 years old.

"The US Food and Drug Administration (FDA) were slower to take action. In January 2003, the FDA had approved fluoxetine as the first such drug for use in pediatric depression, despite only weak data for efficacy. By October 2003, the FDA had issued a ‘Public Health Advisory' alerting physicians to reports of suicidal thinking and suicide attempts. A regulatory authority usually requires proof of efficacy, but in the face of an acknowledged lack of evidence, the FDA reversed the usual burden of proof, stating: ‘failure to show effectiveness in any particular study . . . is not definitive evidence that the drug is not effective’ (Food and Drug Administration, 2003). As Garland (2004) points out, a clinically significant response should be evident in a small trial, but detecting a low-frequency event such as suicidal

Behaviour is difficult in clinical trials. Yet two independent, FDA-commissioned reanalyses of the trial data showed that antidepressants almost doubled the risk of

Suicide-related events compared with placebo (risk ratio 1.81, 95% CI 1.24–

2.64). In October 2004, the FDA instructed manufacturers to include ‘black box’

Warnings on all antidepressants about the risks of suicidal thoughts and behaviours.

Given that SSRIs have been marketed for many years, one might have expected

a warning signal from post-marketing surveillance and reporting systems. "(BRITISH JOURNAL OF P SYCHIATRY, 2005)

Conclusion:

Depression is a serious condition, associated with considerable morbidity and mortality; selective serotonin reuptake inhibitors (SSRIs) were commonly used in its treatment in child and adolescent psychiatry until recently. In the wake of the recent UK Committee on Safety of Medicines (CSM) advice, we conducted a rapid review of current available information on SSRIs and suicidality (suicidal ideation, self-harm and suicide attempt) in children and adolescents from clinical trials and epidemiological studies. There is insufficient safety information from the randomised controlled trials to confirm a definite association between SSRIs and suicidality.

References:

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Elder, G, 1999, 25th Edition, Children of the Great Depression, Westview Press

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