Revised: 20 May 2013

Committees

Excerpt from the draft minutes of the 119th Medicine Adverse Reactions Commitee Meeting (22 SEPTEMBER 2004) relating to antidepressants

Pharmacovigilance issues

3.1 Tricyclic Antidepressants in Children and Adolescents for treating Major depressive Disorder

Reference Material

• Medsafe Report (2004). Tricyclic Antidepressants in Children and Adolescents for treating Major depressive Disorder.
• Hazel et al (2003). Tricyclic drugs for depression in children and adolescents (Review). The Cochrane Database of Systematic Reviews Volume (3) 2003.
• Ray et al (2004). Pharmacoepidemiology and Drug Utilization. Cyclic antidepressants and the risk of sudden cardiac death. Clinical Pharmacology and Therapeutics 2004, 75: 234-241.
• Wilens et al (1996). Cardiovascular effects of Therapeutic Doses of Tricyclic Antidepressants in Children and Adolescents. Journal of The American Academy of Child and Adolescent Psychology 35 (11): 1491-1501.
• Varley, C (2000). Case Study: Sudden death of a child treated with Imipramine. Journal of Child and Adolescent Psychopharmacology 10 (4), 321-325.
• Shah R et al (2001). Deaths from antidepressants in England and Wales 1993-1997: analysis of a new national database. Psychological Medicine 31:1203-1210.
• Drug and Therapeutics Bulletin (2004). Management of bedwetting in children. DTB 42(5): 3-37.
• Faculty of Child and Adolescent Psychiatry-New Zealand Branch (2004). Tricyclic Antidepressants for treating Major Depressive Disorder in Children and Adolescents. Personal Correspondence.

Issue

The purpose of this agenda item was to review the use of the Tricyclic Antidepressants (TCAs) in treating child and adolescent major depressive disorder (MDD). The Committee reviewed the use of SSRI antidepressants in children and adolescents at the March 2004 MARC meeting. Following on from this review, it was considered necessary that the efficacy and safety of TCAs should also be reviewed in detail.

A Medsafe report on TCA use in child and adolescent depression, indicated that current guidelines, reviews, case reports and meta-analyses of published trials, collectively suggest that it is no longer appropriate to use TCA medicines to treat depression in children. The evidence indicates that TCAs are no more efficacious than placebo in treating childhood depression although there is evidence for modest efficacy in treating adolescent depression. In adults there is clear evidence of dose- dependent cardiovascular toxicity associated with TCA use. There is also clear evidence of an effect on heart rate, blood pressure and ECG parameters in children and adolescents. There have been case reports of sudden cardiac death in children taking TCAs at standard doses. It is unclear whether this is an idiosyncratic reaction or is dose dependent as it is for adults. In addition, there is clear evidence that TCAs are more dangerous in overdose than the SSRIs, making the TCAs less preferred in patients at a greater risk of accidental or intentional overdose.

The New Zealand data sheets for amitriptyline, nortriptyline, doxepin, dothiepin, desipramine and trimipramine specifically state that their products are not recommended for use in children. The data sheets for clomipramine, imipramine, maprotriline and mianserin provide specific dosage instructions for children. None of the New Zealand TCA data sheets recommend the use of their product in children aged less than 5 years.

A submission from the New Zealand Branch of the Faculty of Child and Adolescent Psychiatry states that TCAs have no place in the treatment of depression in pre-pubertal children. However, it considers that that the "TCAs have a limited place in the treatment of MDD in older adolescents where their clinical presentation has significant features of psychomotor retardation and/or psychosis".

Discussion

The Committee reviewed the reports and literature provided on this issue. Members noted that there is inadequate evidence of efficacy for the use of TCAs to treat MDD in children and in view of the clear evidence of potential harm; the risk/benefit ratio is unfavourable for children with depression. Members noted that there is some evidence of efficacy in the treatment of adolescent MDD, and agreed that it may be appropriate to prescribe a TCA in this age group but only if the adolescent is under the care of a specialist.

Members commented that although there are no clinical trial data to suggest an increased risk of suicidality with the TCAs, there is also no adequate data to exclude this possible risk. It is unlikely that future studies will be undertaken to address this issue in view of the demonstrated superiority of fluoxetine over the TCAs in the treatment of adolescent depression.

Members also reviewed the DTB article on the management of bedwetting in children. Members noted that it was concluded that the risk/benefit ratio for imipramine in the treatment of enuresis is also generally unfavourable.

The Committee concluded that the TCAs have an unfavourable risk/benefit profile and thus should not be used to treat children with MDD or enuresis. TCAs should only be prescribed to adolescents with MDD if under the care of a specialist.

Recommendation

The Committee recommended that a "Dear Doctor letter" be written to inform prescribers of the MARC's advice on the use of TCAs to treat child and adolescent depression. The letter should also inform prescribers that the MARC considers the risk/benefit profile of these medicines to be unfavourable in the treatment of enuresis.

The Committee recommended that Medsafe write to the product sponsors of all TCAs requesting that the data sheets be amended to state "TCAs are not recommended for use in treating MDD in people under 18 years of age". The Committee also recommended that Medsafe seek permission from the DTB to publish their article on the management of bedwetting.

3.2 Antidepressants and Suicide Warnings

Reference Material

• Medsafe Report (2004). Antidepressants and Suicide Warnings
• FDA Public Health Advisory (March 22^nd 2004). Worsening depression and suicidality in patients being treated with antidepressant medication.
• PAXIL Dear Health Professional Letter (May 2004).
• Jick H et al (2004). Antidepressants and the risk of suicidal behaviours. JAMA 292:338-343
• Wessley S and Kerwin R (2004). Editorial: Suicide Risk and the SSRIs. JAMA 292:379-381.

Issue

The purpose of this agenda item was to review the content of all New Zealand antidepressant data sheets (including SSRIs, TCAs, SNRIs and MAOIs) with respect to suicide warnings.

This item was brought to the Committee's attention for the following reasons:

1. US and Canadian regulators have recently required that a generic suicide warning statement be placed in the product information of all SSRI antidepressants.
2. Recent literature has supported the premise that depressed patients are at the greatest risk of suicide in the early stages of treatment regardless of which antidepressant is prescribed.

The MARC has considered the issue of increased risk of suicidality with the SSRI antidepressants on a number of occasions. A Prescriber Update article was published in 2002 indicating that reports of increased suicidal preoccupation had occurred in adults taking SSRI antidepressants. The MARC has also specifically reviewed the issue of suicidality with SSRIs in child and adolescent major depression. (See Minute item 3.3 for discussion on this issue).

A recent case-control study by Jick, Kaye & Jick (2004), published in JAMA used the UKGPRD database to assess the risk of suicidal behaviours in patients prescribed 2 types of SSRI antidepressants and 2 types of TCAs. The results indicated that there was no significant difference in the risk of suicidal events amongst the users of the four different study antidepressants. The study also documented that suicidal events were more likely to occur within the first month after receiving a first prescription, and especially, within the first 1-9 days. The authors suggest that this probably reflects the fact that antidepressant treatment is not immediately effective, and hence there is a higher risk of suicidal behaviour in newly diagnosed and treated patients compared to those who have been treated for a longer period of time.

A JAMA editorial discussing the Jick et al (2004) study notes that of the 15 adolescent suicides recorded from 1993-1999, in the UKGPRD, none of these adolescents were prescribed an antidepressant. It is relevant that no adolescent prescribed an antidepressant in the study completed suicide.

Medsafe recommends that product sponsors of all antidepressants be requested to update their respective datasheets to include a generic warning statement similar to that required by the FDA. This statement warns about the possibility of worsening depressive symptoms early in treatment (which may or may not be related to the medicine), and the need to monitor patients carefully.

Discussion

The Committee noted that the New Zealand antidepressant datasheets contain highly variable information on the need to monitor patients for worsening depression and/or emerging suicidality in the early stages of treatment.

Members noted the findings of the Jick et al (2004) study and agreed that depressed patients are likely to remain at risk of suicide until their depression is adequately treated. There may be a significant delay in clinical response from the date of initiating antidepressant treatment and it is crucial that all patients, regardless of which antidepressant they are prescribed, are monitored carefully during this time period.

The Committee agreed that the product sponsors for all antidepressants in New Zealand should be required to include a warning statement in their datasheets in line with the Medsafe recommendation above.

Recommendation

The Committee recommended that Medsafe write to the product sponsors of all antidepressants including SSRIs, TCAs, SNRIs and MAOIs, requesting that a generic suicide warning statement be included in their product data sheets.

3.3 SSRI's in Children and Adolescents with Major Depression

Reference material

• March J et al (2004). Fluoxetine, Cognitive-Behavioral Therapy, and Their Combination for Adolescents With Depression. Treatment for Adolescents With Depression Study (TADS). Randomized Controlled Trial. JAMA 292(7): 807-820.
• Glass R (2004). Treatment of Adolescents With Major Depression. Contributions of a Major Trial (Editorial). JAMA 292(7): 861-863.
• Notes from joint meeting of the FDA Psychopharmacologic Drugs Advisory Committee and the Paediatric Advisory Committee 13 and 14 September 2004.
• FDA Statement on Recommendations of the Psychopharmacologic Drugs and Pediatric Advisory Committees. September 16, 2004

Issue

The purpose of this agenda item was to update the Committee on recent international regulatory activity and recent international literature on this issue. The Committee was asked to comment on what regulatory action, if any, should be undertaken in New Zealand.

In March 2004, the Medicines Adverse Reactions Committee (MARC) reviewed the safety of SSRIs in the treatment of child and adolescent depression. The Committee concentrated on a potential increased risk of suicidality with these medicines. At that time the MARC examined reports from the UK CSM, the American College of Neuropsychopharmacology, US Food and Drug Administration (FDA) advisory committees, and the Royal Australian and New Zealand College of Psychiatrists. Although the Committee considered that the available evidence was inconclusive, they recommended that a Dear Health Professional letter be distributed to all prescribers emphasising the need to seek specialist advice before prescribing any antidepressant to children under the age of 18 years. It also reinforced the need to monitor all patients with depression for the emergence or worsening of suicidal thoughts and behaviours.

At the conclusion of the March meeting, members agreed to review this issue again after the results of the FDA commissioned re-analysis of the raw data from paediatric clinical trials was completed. The FDA published the results of the Columbia University reanalysis of paediatric clinical trial data in August 2004. The re-analysis showed that when combining the results from all trials, patients taking an SSRI or an SNRI were 1.78 (CI 95%, 1.14-2.77) times more likely to experience serious suicide-related events than patients taking placebo. There was no significant increased risk of these events from analysis of the SSRI-only trials in MDD. Only fluoxetine was shown to have efficacy. It was noted that no patients had committed suicide in any of the clinical trials.

A joint meeting of the FDA Psychopharmacologic Drugs Advisory Committee and the Paediatric Advisory Committee was held on 16-17 September 2004. The Advisory Committees concluded the following:

• The finding of an increased risk of suicidality in paediatric patients applied to all the drugs studied (Prozac, Zoloft, Remeron, Paxil, Effexor, Celexa Wellbutrin, Luvox and Serzone) in controlled clinical trials;
• Any warning related to an increased risk of suicidality in paediatric patients should be applied to all antidepressant drugs, including those that have not been studied in controlled clinical trials in paediatric patients, since the available data are not adequate to exclude any single medication from an increased risk;
• Endorsed a patient information sheet ("Medication Guide") to be provided to the patient or their caregiver with every prescription;
• Recommended that the products not be contraindicated in the US because the Committees thought access to these therapies was important for those who could benefit; and
• Recommended that the results of controlled paediatric trials of depression be included in the labelling for antidepressant drugs.

Discussion

Members were reminded that in New Zealand, none of the SSRIs have ever been approved for use in treating MDD in children and adolescents.

The Committee noted that the reanalysis of paediatric clinical trial data undertaken by Columbia University was in broad agreement with the previous conclusions drawn by the FDA Office of Drug Safety. Members discussed the recommendations of the joint FDA advisory committee and noted that there was a recommendation not to contraindicate the use of SSRIs in children and adolescents.

The Committee also discussed the significance of the March J et al (2004) TADS study recently published in JAMA. Members agreed that this study provides good evidence of efficacy for fluoxetine in treating child and adolescent depression and also the appropriateness of using fluoxetine as first-line treatment. The synergistic effect of fluoxetine plus Cognitive Behavioural Therapy (CBT) in combination was noted. However members stated that in view of the limited availability of CBT in New Zealand, this combination is unlikely to be used extensively in clinical practice.

Members expressed concern that any advice on the risk of suicidality in children and adolescents taking SSRIs may inadvertently support the prescription of TCAs in this age group. It was agreed that the MARC advice must include risk/benefit statements with respect to both the SSRIs and the TCAs.

After review of the literature provided on this issue as well as that provided in agenda items 3.1 and 3.2 the MARC concluded the following:

• There is some evidence of an increased risk of suicidality with the use of all SSRI's in children and adolescents.
• It is unknown if the TCAs confer a similar risk of suicidality as studies have not been undertaken to address this issue.
• There is no evidence of efficacy for the TCAs in the treatment of depression in children.
• Fluoxetine is the only SSRI for which there is evidence of efficacy in the treatment of child and adolescent depression. There is no evidence of efficacy for the other SSRIs from meta-analyses of randomised controlled trials.
• The risk/benefit analysis for the use of SSRIs in adults remains positive.
• The MARC accepts that it may still be appropriate to use these agents in individual cases (such as treatment resistant depression) when under the care of relevant specialists.
• SSRIs are less dangerous in overdose than other classes of antidepressants.
• The MARC aims to support the safe use of these medicines by way of improved warnings in the product data sheets and consumer medicine information, and by asking Medsafe to issue a "Dear Health Professional" letter to all prescribers.

The MARC still considers that the data on SSRIs and suicidality are inconclusive in establishing the strength of this association. The MARC maintains a high priority on reviewing the safety of all antidepressant medicines as more data becomes available.

Recommendations

The Committee recommended that a "Dear Health Professional" letter be written to inform prescribers of the MARC's advice. The Committee recommended that the letter be peer reviewed by MARC members, and a representative from the faculty of Child and Adolescent Psychiatrists.

The Committee also recommended that Medsafe contact the product sponsors for all the SSRIs to request that specific mention of randomised controlled trials in paediatric populations be included in the product data sheets. This is in addition to requests for generic warning statements on the risk of suicidality as outlined in minute item 3.2.