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 β-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,

α-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.

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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

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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 α-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

cleft by binding at the 5-HT reuptake transporter preventing reuprake and subsequent

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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.

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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

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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

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 α-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 drug’s 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 α-2 adrenergic receptor antagonists, serotonin 5-HT2 or 5-

HT3receptor 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’

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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.

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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. Today’s

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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