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Abstract
Suicide is a world wide problem. Although suicide is a relatively rare event, it takes high importance because of its impact on family and every body who may concern. Suicide is a catastrophic human event; an ending of life by the person’s own hands is shocking to families, friends and caretakers. It is the result of multidimensional factors, including psychiatric medical, genetic, familial, occupational, environmental, social and cultural factors. Stressful life events have a significant association with completed suicides. Although some people may attempt or commit suicide out of the blue mostly there is an underlying psychiatric disorder. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.
Every psychiatric patient must be assessed for the risk of suicide. This assessment should include psychiatric evaluation for risk factors of suicide such as history of suicidal attempt, ideas or plans for suicide, sense of hopelessness or helplessness and a positive family history of suicide, and protective factors such as religiosity and the presence of social support . Suicidal risk assessment scales should be used as a supplementary tool in assessment as they help uncovering suicidal ideas in some patients. So, modifiable, treatable risk factors can be identified and the patient’s safety requirements determined.
Systematic suicide risk assessment is a complex, difficult, and challenging clinical task. In addition to the rarity of the event, it is difficult and sometimes impossible to predict suicide in certain patients, patient may hides his intent of suicide (some patients consider the treating psychiatrist as an enemy) and no collateral source of information is available, on other occasions the patient is unreliable. Sometimes the idea of suicide comes suddenly and the patient acts on it. Suicidal risk assessment scales are mostly poor predictors of suicide so repeated clinical assessment of the patient is the mainstay for follow up of the patient progress. Attempts to predict who will commit suicide lead to a large number of false-positive and false-negative predictions. Suicide risk factors occur in many depressed patients who do not commit suicide. No method of suicide risk assessment can reliably identify who will commit suicide and who will not.
Depressed individuals have a much higher risk of suicide. Depression as well as a number of other disorders has become more treatable disorders, depression was considered by the mental health professionals as a treatable risk of suicide. The primary treatment for depression involves the use of antidepressant drugs, so, it is important that clinicians become familiar with this important group of drugs. Although primarily used for the treatment of depression, drugs within this category also have a number of other important uses such as anxiety disorders.
Antidepressants are classified into many classes according to their mechanism of action, these classes include;
1) Tricyclic antidepressants (TCA); which include amitriptyline, imipramine, clomipramine, doxepin, desipramine, notriptyline, protriptyline, trimipramine, amoxapine and maprotiline. TCA act by blocking the reuptake pumps for both serotonin and norepinephrine and, to a lesser extent dopamine.
2) Selective serotonin reuptake inhibitors (SSRIs); which include fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram and escitalopram. SSRIs are more potent and more selective serotonin reuptake inhibitors than the most of TCA.
3) Serotonin and norepinephrine reuptake inhibitor (SNRIs); Venlafaxine is a specific SNRI it has mild dopamine reuptake activity but at highest doses. Doluxetine and desvenlafaxine are newly developed SNRIs.
4) Dual serotonin 2 antagonists/ serotonin reuptake inhibitors (SARI); Include trazodone and nefazodone which are powerful 5HT2a antagonists and, to a lesser extent 5HT reuptake inhibitors.
5) Noradrenergic reuptake inhibitor (NRIs); Reboxetine which act by inhibit norepinephrine reuptake in the synaptic cleft and indeed anywhere norepinephrine is released.
6) Noradrenergic and specific serotonergic antidepressants (NaSSA); Mirtazapine which acts by boosting both serotonin and norepinephrine levels through the antagonism of alpha2 autoreceptors involved in the inhibition of both 5HT and NE release.
7) Norepinephrine and dopamine reuptake inhibitors (NDRIs); Bupropion which has a weak DRI properties and even a weaker NRI actions but it is the NRI activity of its metabolite that is most powerful.
8) Serotonin uptake enhancers; tianeptine, it acts by enhancing 5HT reuptake at the synapse. Its mechanism of antidepressant efficacy is unclear; some data suggest that tianeptine enhances dopaminergic tone but, not through inhibition of dopamine reuptake.
9) Monoamine oxidase inhibitors (MAOIs); Which include;
a) Irreversible MAOIs; include phenelzine, tranylcypromine, and isocarboxazid which work by inhibiting the enzyme (monoamine oxidase) that breaks serotonin, norepinephrine and dopamine in the synaptic cleft. They are irreversible inhibitors of both A and B enzyme subtypes.
b) Reversible MAOIs; moclobemide (RIMA) selective for A enzyme sub-type. And deprenyl selective for B enzyme sub-type.
Efficacy of antidepressants is variable in the different age groups. In adults; the efficacy of the different classes of antidepressants in major depression is well established and SSRIs are preferred as first line because of a relatively good side effects profile. In Children and Adolescents; TCAs showed no efficacy in the treatment of major depressive disorder (MDD), and similar results for SNRIs and mirtazapine. For SSRIs; only flouxetine showed good evidence, citalopram showed contradictory evidence, paroxetine showed no evidence and sertraline showed modest evidence of efficacy for the treatment of MDD.
Despite this, the use of antidepressants in pediatric patients, particularly the selective serotonin reuptake inhibitors (SSRIs) and the atypical antidepressants, has rapidly increased recently, in part, because of their favorable side effects profile compared to earlier families of antidepressants such as the tricyclic antidepressants(TCA). Much of the use of antidepressants in pediatric populations with affective disorders has occurred ”off-label” without adequate testing regarding their safety and efficacy. Only, fluoxetine, has FDA approval for the treatment of depression in children and adolescents.
Recently, the safety of SSRIs, SNRIs and other novel agents has been questioned, in regards to their potential to cause or exacerbate aggression and suicidality (defined as emergence and/or worsening of suicidal thoughts, behaviours and attempts). Initially these reports dealt with adult patients but subsequently the controversy has focused mainly on children and adolescents, this is a major health issue, given the increasing prevalence of depression in children and adolescents and the established failure of tricyclic antidepressants to perform effectively in this population.
In March 2004, the U.S. Food and Drug Administration (FDA) issued a public health advisory regarding worsening depression and suicidality in pediatric and adult patients being treated with 10 newer antidepressants (bupropion, citalopram, fluoxetine, fluvoxamine, mirtazapine, nefazodone, paroxetine, sertraline, escitalopram, and venlafaxine). The March 2004 advisory recommended close observation for the emergence of suicidality in all patients treated with antidepressants, especially at the time of treatment initiation or dose increase.
The United Kingdom Committee on Safety of Medicines (CSM) first raised concerns about suicide risk in 2003 after reports of self-harm and potentially suicidal behavior in adolescents treated with paroxetine. Subsequent reanalyses of clinical trial data indicated higher rates of “possibly suicide-related events” in adolescents treated with several newer antidepressants.
After reviewing these data in February 2004, the FDA advisory committee commissioned a reevaluation and reanalysis of data from all pediatric antidepressant trials. This meta-analysis found a significantly higher risk of suicidal behavior in children and adolescents treated with newer antidepressants than in those who received placebo, and the FDA advisory committee recommended a “black box” warning regarding risk of antidepressant use in children and adolescents. A requirement for a “black box” warning for all antidepressants was issued in October 2004. The March 2004 FDA advisory acknowledged that the available data did not indicate any increased risk in adults treated with antidepressants.
The primary source of evidence that made the FDA require the black box warning was a meta-analysis of 24 randomized placebo controlled trials designed to assess the efficacy of antidepressants for different psychiatric disorders in children and adolescents. The FDA examined studies of both selective serotoniin reuptake inhibitors (SSRIs) and atypical antidepressants, but did not consider older classes of antidepressants such as tricyclics and monoamine oxidase inhibitors (MAO1s). There were no completed suicides. The overall rate of suicidal ideation and/or behavior, however, was significant (1.7%).These disappointing results appeared after Meta analysis of both published and unpublished randomized controlled trials, this situation raised concern about research ethics and regulations.
Meta analysis of many randomized controlled trials (RCTs) in addition to retrospective cohort studies showed a risk of suicidal act with antidepressants treatment especially in children and adolescents and to less extent in adults. Taking into account that suicidal patients are usually excluded from RCTs, for a relatively rare event like suicidal act to appear in RCTs means significance. On the other hand, a study of 24119 adolescents aged 12-18 years treated for major depression showed no suicidal risk and many retrospective cohort studies and few RCTs linked increased rate of prescription of antidepressants to reduction of suicide rate.
Different mechanisms have been proposed whereby antidepressant treatment might lead to suicidal act, by simply ameliorating psychomotor retardation before depressed mood so, the patient acts on his suicidal ideation; by an action intrinsic to the specific antidepressant; by toxicity in overdose; 2ry to poor compliance to treatment; due to poor efficacy of antidepressants or wrong diagnosis (mixed depression).
The current evidence shows that the risk-benefit ratio for newer antidepressants appears to be different for different age groups and also between different medications. The magnitude of the elevated risk in children and adolescents in RCTs must be considered relative to any potential benefits of treatment, which have been shown only for fluoxetine.
For adults and the elderly there is a modest contradictory evidence of risk and efficacy is proved resulting in a good benefit risk ratio except for young aduls (less than 25 yrs) because inspite of proved efficacy there is a recent evidence of increased risk of suicidal ideation and /or behavior with antidepressants in this age group.so its situation is better than children and adolescents but worse than old adult group. All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.
It is important here to keep in mind two points, first; the risk of suicidal acts in all age groups is still a matter of controversy Second; the evidence for the efficacy of antidepressants in the treatment of anxiety disorder in children and adolescents is good, resulting in better benefit risk ratio than in depression.
More RCTs to assess the efficacy and risk of suicide with antidepressants in children and adolescents are needed. These trials should be under observation of the regulatory agencies to avoid selective publication.