Antidepressant 1

Antidepressant
• Symptoms of depression include intense feelings of sadness, hopelessness & despair as well as the inability to experience pleasure in usual activities, changes in sleep patterns & appetite, loss of energy & suicidal thoughts.
• Mania is characterized by the opposite behavior including enthusiasm, rapid thought & speech patterns, extreme self-confidence & impaired judgment.
Note: Depression & mania are different from schizophrenia (which produces disturbances in thought).

Mechanism of antidepressant drugs
• Potentiate, either directly or indirectly, the actions of norepinephrine (NE) and/or serotonin (5-HT) in the brain.
• This, along with other evidence, led to the biogenic amine theory, which
proposes that depression is due to a deficiency of monoamines, such as NE & 5-HT, at certain key sites in the brain.
• Conversely, the theory proposes that mania is caused by an overproduction of these neurotransmitters.
• However, the amine theory fails to explain why the pharmacologic effects of any of the antidepressant & anti-mania drugs on neurotransmission occur immediately, whereas the time course for a therapeutic response occurs over several weeks.
• Potency of the antidepressants (blocking neurotransmitter uptake) often does not correlate with clinically observed antidepressant effects.
• This suggests that decreased uptake of the neurotransmitter is only an
initial effect of the drugs, which may not be directly responsible for the antidepressant effects.
• It has been proposed that use of antidepressants over a 2 - 4 week result in down-regulation of presynaptic inhibitory receptors in the brain, this in turn permits greater synthesis & release of neurotransmitters.

1. Selective serotonin reuptake inhibitors (SSRIs)
• Inhibit serotonin reuptake, having 300 – 3000 fold greater selectivity for the 5-HT transporter, as compared to the NE transporter.
Note: tricyclic antidepressants (TCAs) nonselectively inhibit the uptake of both
NE & 5-HT.
• Both SSRIs & TCAs exhibit little ability to block the dopamine transporter.
• Have little blocking activity at muscarinic, ?- adrenergic & histaminic H1 receptors.
• Therefore, common side effects associated with TCAs, such as orthostatic
hypotension, sedation, dry mouth & blurred vision, are not commonly seen
with the SSRIs.
• Relatively safe even in overdose, thus they have largely replaced TCAs & monoamine oxidase inhibitors (MAOIs) as the drugs of choice in treating depression.
• SSRIs include fluoxetine (prototypic drug), citalopram, escitalopram, fluvoxamine, paroxetine & sertraline.
• Escitalopram is the pure S-enantiomer of citalopram.

Actions
• Block 5-HT reuptake increasing its concentrations in the synaptic cleft & ultimately, to greater postsynaptic neuronal activity.
• Antidepressants, including SSRIs, typically take at least 2 weeks to produce significant improvement in mood & maximum benefit may require up to 12 weeks or more.
• However, none of the antidepressants are uniformly effective.
• Approximately 40 % of depressed patients treated with adequate doses for 4 - 8 weeks do not respond to the antidepressant agent.
• Patients who do not respond to one antidepressant may respond to another & approximately 80 % or more will respond to at least one antidepressant drug.
Note: These drugs do not usually produce CNS stimulation or mood elevation
in normal individuals.

Therapeutic uses
1. Depression, for which they are as effective as the TCAs.
2. Other psychiatric disorders, including obsessive-compulsive disorder, panic disorder, generalized anxiety disorder, posttraumatic stress disorder, social anxiety disorder, premenstrual dysphoric disorder & bulimia nervosa (only fluoxetine is approved for this last indication).
Pharmacokinetics
• Well absorbed after oral administration.
• Food increase the absorption of sertraline.
• Only sertraline undergoes significant 1st pass metabolism.
• The majority of SSRIs have plasma half-lives that range between
16 & 36 hours.
• Metabolized in to inactive metabolites.

Fluoxetine differs from the other members of the class in two respects:
1. Has a much longer half-life (50 hours) & is available as a sustained-release preparation allowing once-weekly dosing.
2. Its metabolite S-norfluoxetine has long half-life (10 days) & as potent as the parent compound.
• Fluoxetine & paroxetine are potent inhibitors of a hepatic CYP450 isoenzyme, interfering with the elimination of TCAs, neuroleptic drugs & some antiarrhythmic & ?-adrenergic antagonists.
Note: About 7 % of the Caucasian population lacks this P450 enzyme (referred as “poor metabolizers”) & therefore, metabolize fluoxetine & other substrates of this enzyme very slowly.
• Other cytochrome enzymes involved in the metabolism of SSRI & multiple medications may also be inhibited by the SSRIs.
• In addition to renal excretion, paroxetine & sertraline also undergo fecal excretion (35 & 50 %, respectively).
• Hepatic impairment necessitates dosages adjustment of all of these drugs.


Adverse effects:
• Fewer & less severe adverse effects than the TCAs & MAOIs.
• Although they may cause headache, sweating, anxiety & agitation, GI effects (nausea, vomiting, diarrhea), weakness & fatigue, sexual dysfunction, weight changes, sleep disturbances (insomnia & somnolence) & the above-mentioned potential for drug-drug interactions.

1. Sleep disturbances:
• Patients with difficulty sleeping may benefit from the more sedating than activating antidepressants (Paroxetine & fluvoxamine).
• Fatigued patients or who are complaining of excessive somnolence may benefit from the more activating antidepressants (eg. fluoxetine or sertraline).

2. Sexual dysfunction:
• Loss of libido, delayed ejaculation & anorgasmia.
SSRI-induced sexual dysfunction can be managed by:
a- Replacement by other antidepressant which having fewer sexual side effects, such as bupropion or mirtazapine.
b- Alternatively, the dose of the drug may be reduced.
c- Treatment with sildenafil, vardenafil, or tadalafil may improve erectile dysfunction.

3. Use in children and teenagers:
• Antidepressants should be used cautiously in children & teenagers (due to suicidal ideation ) & they should be observed for worsening depression & suicidal thinking.
• Fluoxetine, sertraline & fluvoxamine are approved by FDA for use in children to treat obsessive-compulsive disorder & fluoxetine is approved to treat childhood depression.

4. Overdoses:
• Large intakes of SSRIs do not usually cause cardiac arrhythmias (as TCAs do), but seizures are a possibility because all antidepressants may lower the seizure threshold.
• All SSRIs have the potential to cause a serotonin syndrome that may include the symptoms of hyperthermia, muscle rigidity, sweating, myoclonus (clonic muscle twitching) & changes in mental status & vital signs when used in the presence of a MAOI or other highly serotonergic drug.
• Therefore, extended periods of washout for each drug class should occur prior to the administration of the other class of drugs.

5. Discontinuation syndrome:
• Whereas all of the SSRIs have the potential for causing a discontinuation syndrome after their abrupt withdrawal, this risk is higher with agents having shorter half-lives & inactive metabolites.
• Fluoxetine has the lowest risk of causing an SSRI discontinuation
syndrome.
• Signs & symptoms of serotonin-related discontinuation syndrome include headache, malaise & flu-like symptoms, agitation & irritability, nervousness & changes in sleep pattern.

2. Serotonin / Norepinephrine reuptake inhibitors (SNRIs) include:
Venlafaxine, desvenlafaxine & duloxetine
• Inhibit the reuptake of both 5-HT & NE. They, termed selective 5-HT / NE reuptake inhibitors (SNRIs).
• Effective in treating depression unresponsive to SSRIs.
• Furthermore, depression is often accompanied by chronic painful symptoms, such as backache & muscle aches, against which SSRIs are also relatively ineffective. This pain is, in part, modulated by 5-HT & NE pathways in the CNS.
• Both SNRIs & TCAs, are sometimes effective in relieving physical symptoms of neuropathic pain such as diabetic peripheral neuropathy.
• However, the SNRIs, unlike the TCAs, have little activity at adrenergic, muscarinic, or histamine receptors and, thus, have fewer adverse effects than the TCAs.
• Abrupt withdrawal of SNRIs may precipitate a discontinuation syndrome.

A. Venlafaxine and desvenlafaxine

Venlafaxine
• Potent inhibitor of 5-HT reuptake & at medium to higher doses, is an inhibitor of NE reuptake.
• It is also a mild inhibitor of dopamine reuptake at high doses.
• Has minimal inhibition of the CYP450 isoenzymes.
• Half-life of the parent drug & its active metabolite is about 11 hours.

Desvenlafaxine
• Active, demethylated, metabolite of venlafaxine.
• Common side effects are nausea, headache, sexual dysfunction, dizziness, insomnia, sedation & constipation.
• At high doses, there may be an increase in BP & HR.

B. Duloxetine
• Inhibits 5-HT & NE reuptake at all doses.
• Should not be administered to patients with hepatic insufficiency or with end-stage renal disease.
• Food delays its absorption.
• Side effects:
1. GI side effects are common including nausea, dry mouth & constipation. Diarrhea & vomiting are seen less often.
2. Insomnia, dizziness, somnolence & sweating.
3. Sexual dysfunction.
4. Possible risk for an increase in either BP or HR.