Chapter I 1.

1 Introduction There is a great concern that antidepressant used in children and adolescents may paradoxically increase their risk of suicidal thoughts and behavior. Twenty-five years ago, long before the introduction of SSRI, the adolescent suicide rate was increasing rapidly, having tripled over the previous 2 decades but the risk factors involved were unknown. Today young people with high suicide risk are able to be identified and empirically validated treatments are offered for depression.1 1.1.1 Changes in Brain of Patients With Depression Indicative of Antidepressants In the brains of the patients with depression who committed suicide, it is found that there is an increased density of -adrenoceptors in the cortical regions and 5-hydroxytryptamine (5-HT2a) receptors in the limbic regions. There is also an increased density of muscarinic receptor in the limbic regions. In contrast, the concentration of 5-hydroxyindole acetic acid (5-HIAA) is decreased in several brain regions. 4 1.1.2 General Mechanisms Of Antidepressants One of the mechanisms are norepinephrine transporter blockade. There may be changes in cholinergic and aminergic receptors in depression following some antidepressant treatment. Central muscarinic receptors are supersensitive in patients with depression and chronic treatment with antidepressant normalize this supersensitivity and this effect does not depend on any intrinsic anticholinergic activity of antidepressant. There may also be changes in serotonergic function involving serotonin reuptake inhibition following antidepressant treatment which will be discussed later. Other mechanisms are dopamine reuptake inhibition, histamine H1 receptor blocker, -1 adrenergic receptor blockade, dopamine D2 receptor blockade and muscarinic acetylcholine receptor blockade.

Chronic antidepressant treatments have been shown to reduce the behavioral effect of N-methyl-D-aspartate (NMDA)-glutamate receptor antagonist dizolcipine. Therefore, it will reduce the excitatory glutamate transmission that is mediated by NMDA receptors. There are also adaptive changes in the glucocorticoid receptors following antidepressant treatment. For example, chronic administration of imipramine increases glucocorticoid receptors particularly the noradrenergic and serotonergic cell body regions. Antidepressants can also affect the endocrine-immune functions. Another mechanism of antidepressant is inhibiting neurite outgrowth from nerve cells. A common mode of action of all antidepressants is to modify the actual structure of nerve cells and eliminate inappropriate synaptic contacts that are responsible for behavioral and psychological changes associated with depression. 4

Chapter II 2.1 Selective Serotonin Reuptake Inhibitor (SSRI) Serotonin reuptake inhibitors have replaced the tricyclic antidepressants in the United States. Fluoxetine (Prozac) was introduced in 1988 and was followed by sertraline (Zoloft), paroxetine (Paxil), fluvoxamine (Luvox), citalopram (Celexa) and escitalopram (Lexapro). All but fluvoxamine are approved by the US FDA for treating depression. Fluvoxamine is only approved for obsessive compulsive disorder.2 2.1.1 Mechanism of SSRI Serotonin reuptake inhibitors selectively block serotonin reuptake at the presynaptic nerve terminal. Citalopram and escitalopram have the most selective effect on serotonin reuptake with little inhibitory effect on norepinephrine and dopamine reuptake and a low affinity for -1 adrenergic receptors, muscarinic cholinergic receptors and histamine H1 receptors. Other SSRI have similar profiles except that paroxetine has some anticholinergic properties, fluoxetine weakly inhibits norepinephrine reuptake and sertraline weakly inhibits norepinephrine and dopamine reuptake. There is experimental evidence that the chronic administration of antidepressants or electroconvulsive therapy (ECT) enhances the inhibitory effect of microiontophoretically applied 5-HT. This effect is blocked by lesions of the noradrenergic projections to the frontal cortex. SSRIs after chronic administration down-regulate the inhibitory 5-HT1a receptors on the serotonergic cell body leading to an enhanced release of the transmitter from the nerve terminal. Serotonin can also cause decrease dopamine release from the substantia nigra. Some SSRIs cause dystonias and precipitate the symptoms of parkinsonism if given to patients who are responding to L-dopa. Sertraline appears to differ from other SSRIs in this respect and may slightly enhance dopaminergic function by reducing reuptake of this transmitter. Depression is associated with reduced levels of the monoamines in the brain, such as 5-HT. The SSRIs are thought to restore the levels of 5-HT in the synaptic
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cleft by binding at the 5-HT reuptake transporter preventing reuprake and subsequent degradation of 5-HT. This reuptake blockade leads to the accumulation of 5-HT in the synaptic cleft and the concentration of 5-HT returns to within the normal range. This action of SSRIs is thought to contribute to the alleviation of the symptoms of depression. In the presence of the SSRI, small amounts of 5-HT continue to be degraded in the synaptic cleft. 2

Figure 1. The mechanism of action of specific 5-HT reuptake inhibitors 2.1.2 Side Effects of SSRI SSRI are generally well tolerated. However, approximately 15% of the patients cannot tolerate certain side effects and therefore may stop taking the drug. A major issue concerning adverse effect of antidepressant is their effect on compliance which may limit the effectiveness of the treatment and thus prolong the depression, leaving the individual at risk of suicide. The potential of different antidepressants to

cause side effects varies greatly. However, tolerance occurs to many of the adverse effects of antidepressants. Tolerance soon occurs to the nausea caused by the SSRIs.

Serotonin Reuptake Inhibition Anorexia early in the treatment and weight gain later Dose-dependent increase or decrease in anxiety Ejaculatory disturbances, anorgasm, and decreased libido Extrapyramidal side effects Interaction with monoamine oxidase inhibitors and tryptophan Nausea, vomiting and diarrhea

Table 1.

Adverse Effects of Antidepressant Drugs Based on Mechanism of Action

Gastrointestinal side effects Sertraline and fluvoxamine may cause more gastrointestinal side effects than other serotonin reuptake inhibitors. Nausea and diarrhea are dose-related and usually resolve within the first 2 weeks of treatment. Starting the medication at low dose and giving it with food usually alleviates nausea. Constipation and dry mouth tend to be more common with paroxetine because of its anticholinergic activity. Anorexia is the most common with fluoxetine and occurs early in the treatment. It is probably related to activation of 5-HT2C receptors. However, with time, this suppressant effect on appetite is lost. Indeed, SSRI have the potential to cause weight gain, possibly due to desensitization and down-regulation of the serotonin receptors associated with appetite control. 2 Central nervous system side effects Patients may experience increased anxiety, most commonly early in treatment. Sleep disturbances, either insomnia or somnolence have been reported in about 25% of patients taking SSRIs. Fluoxetine is more likely to cause insomnia than is paroxetine which is more likely to cause sedation. Others tend to lead equally to somnolence or insomnia. Insomnia can be treated with trazodone, benzodiazepines or other sedative medications. Headache, nightmares and vivid dreams have been reported in a minority of patients. These side effects often resolve within a few weeks and rarely lead to a change in medication. In rare cases, SSRIs can cause extrapyramidal side effects including akathisia. Such adverse effects are not due to dopamine receptor blockade

but rather to the increased serotonin at the synaptic levels, mediating inhibition of the release of dopamine through one of the presynaptic serotonin receptor subtypes. Orthostatic hypotension is unlikely in patients treated with SSRIs because they do not block -1 adrenergic receptors significantly. These drugs have minimal effects on histamine H1 receptors and therefore are less sedating than tricyclic antidepressants. 2 Bleeding SSRIs inhibit platelet function and may prolong bleeding. Several reports have indicated an association between the use of these drugs and bleeding disorders ranging from bruising and epistaxis to more serious conditions such as gastrointestinal bleeding. 2 Hyponatremia Hyponatremia has been reported in rare cases. 2 Serotonin syndrome It results from hyperstimulation of serotonin receptors, and it is characterized by nausea, diarrhea, restlessness, extreme agitation, hyperreflexia, autonomic instability, myoclonus, hyperthermia, rigidity, delirium, seizure and status epilepticus. In severe cases, it can result in cardiovascular collapse, coma and death. This syndrome can occur when monoamine oxidase (MAO) inhibitor is given with a SSRI, pentazocine or L-tryptophan. Therefore, it is mandatory to wait at least 2 weeks after stopping a SSRI before starting a MAO inhibitor and at least 5 weeks if switching from fluoxetine in view of this drugs long half-life. 2 Discontinuation syndrome This syndrome can occur if SSRI with a short half-life such as paroxetine or fluvoxamine is abruptly stopped. Patients may experience dizziness, nausea, weakness, insomnia, anxiety, irritability and headache. These symptoms tend to be transient and resolve spontaneously within a week. Slowly tapering SSRI over a couple of weeks can help prevent this syndrome. Fluoxetine is less likely to cause this syndrome because of its long half-life. Indeed, fluoxetine has been used to treat the discontinuation syndrome caused by other SSRIs. 2 Sexual dysfunction
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Although psychiatric illnesses in themselves can affect sexual desire and performance, so can the drugs used to treat the illness. Sexual dysfunction is the most common side effect of all SSRIs. Delayed ejaculation, anorgasmia and decreased libido can occur in up to 60% of patients and the effects continue as long as the drug is taken. The majority of studies have assessed sexual dysfunction with SSRIs but it is difficult to interpret these findings as the study designs vary considerably. The stimulation of serotonin 5-HT2 and 5-HT3 receptors is a proposed mechanism for the occurrence of sexual dysfunction due to SSRIs, so it has been suggested that adding medications that block those receptors might help with this adverse effect. The most common medication for counteracting this adverse effect fall into 3 groups that is the -2 adrenergic receptor antagonists, serotonin 5-HT2 or 5HT3receptor antagonists and dopaminergic agents. Other strategies include decreasing the dose or by adding bupropion, sidenafil, cyproheptadine or buspirone. Another method include switching to another antidepressant that has few sexual side effects such as bupropion, mirtazapine or nefazodone. 2

Table 2. Assessment of sexual dysfunction of a patient taking a psychotropic drug Assessment of a patient who complains of sexual difficulties while taking a psychotropic drug involves the detailed evaluation of a range of factors as shown in Table 2. above. Several strategies beneficial in treatment include3: Waiting for the development of tolerance Reduction in dosage Delay the taking of the drug until after sexual activity

 drug holidays Adjuvant treatments Changing to a different psychotropic drug Behavioral strategies to improve sexual technique Individual psychotherapy Couple therapy Suicide Risk The relationship between antidepressants especially SSRIs, and suicide ideation and behavior has received considerable public attention lately. The use of these drugs in children and adolescents has been of particular concern. In October 2004, the FDA issued a warning about the increased risk of suicidal thoughts and behavior in children and adolescents being treated with antidepressants. The agency has asked pharmaceutical manufacturers to add a black box warning statement to the label for all antidepressants to describe the risk and emphasize the need for close monitoring of patients started on these medications. If there is an increased risk of suicide, a possible explanation is that SSRIs and some other antidepressants can cause anxiety, agitation and activation particularly at the start of treatment. In someone with lowered mood, new aversive symptoms might further worsen mood and increase the risk of suicide. 2 The new warning does not prohibit the use of antidepressants but warns of the risk of suicidal thoughts and behavior and encourage clinicians to balance the risk with clinical need and closely monitor patients especially at the start of the treatment. This issue remains a concern and a topic of continuing scientific debate. Disentangling the evidence is problematic as much of the research is sponsored by the pharmaceutical industry. The suicide rate has actually been declining over the last 10 to 15 years, coinciding with the introduction of SSRIs and increases in antidepressant prescriptions. Furthermore, most of those who commit suicide and carry the diagnosis of major depressive disorder at the time of death are either untreated or receiving

subtherapeutic doses of antidepressants, indicating the need for better recognition and adequate treatment of patients at risk. It is important to educate patients about their illness and available treatment options. They should be informed about the current controversy regarding the use of SSRIs as a part of the process of obtaining informed consent. They need to be instructed to watch for any signs of activation, agitation or suicidal ideation and inform the prescribing physician immediately. It is also reasonable to schedule more frequent follow-up visits at the beginning of the treatment to monitor more closely for emergence of these side effects. Patients at higher risk for suicide may be given limited amounts of the medication, just enough until the next follow-up visit. Any reports of suicidal ideation need to be taken seriously and hospitalization should be considered. Patient need to be referred for psychiatric consultation if one or more antidepressants fail or produce only a partial response or if they have major depression with psychotic features. 5

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Chapter III 3.1 Summary While SSRIs are demonstrably effective in controlling depressive illness, they must be prescribed with care, for 3 main reasons. One of the reasons is that they can produce adverse effects. The second reason is they may interact with other medication and the third reason is they may cause morbidity or mortality in overdose. The most notable problem about adverse effects is that they may hinder compliance or lead to subtherapeutic prescribing and thus defeat the object of treatment. Some interactions are potentially serious and prescribers need to be aware of potential pitfalls. Todays psychiatrist needs to be more of a physician and pharmacologist than his predecessor. Patient education is also very important because education and reassurance of patients about side effects will enhance compliance and improve treatment outcome. Providing patients with contact information might decrease their anxiety and help in reporting any adverse event. It is also very helpful to provide patients with literature explaining the potential side effects. Patients should be encouraged to contact their provider about any troublesome side effect that does not resolve. 6

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References :-

1. Brent David A. Antidepressants and Pediatric Depression The Risk of Doing Nothing. NEJM. 2004;315:1598-1601

2. Khawam Elias A.; Georgia Laurencic; Malone Jr. Donald A. Side Effects of Antidepressants: An Overview. Cleveland Clin Journal of Med. 2006;73:351-361

3. Baldwin David and Mayers Andrew. Sexual Side Effects of Antidepressant and Antipsychotic Drugs. Advances in Psychiatric Treatment. 2003;9:202-210

4. Leonard Brian. Clinical Implications of Mechanisms of Action of Antidepressants. Advances in Psychiatric Treatment. 2000;6:178-186

5. Gunnell David and Ashby Deborah. Antidepressants and Suicide: What is the Balance of Benefit and Harm? BMJ 2004;329:34-38

6. Henry John A. Toxicity of Newer Versus Older Antidepressants. Advances in Psychiatric Treatment. 1997;3:41-45

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