Antidepressant 1
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Dr.Entisar Al-Mukhtar
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, t,
rapid thought & speech patterns, extreme self-confidence & impaired
judgment.
Mechanism of antidepressant drugs
• Antidepressants potentiate, either directly or indirectly NE & /or 5-HT
actions in the brain.
• The pharmacological effects of the antidepressant & antimania drugs on
neurotransmission occur immediately; however, therapeutic response
occurs over several weeks.
• the use of antidepressants over a 2 - 4 week result in down-regulation of
presynaptic inhibitory receptors permitting greater synthesis & release of
neurotransmitters.
1. Selective serotonin reuptake inhibitors (SSRIs)
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Inhibit 5-HT reuptake, having 300 – 3000 fold greater selectivity for 5-HT
transporter, as compared to the NE transporter.
Note: Tricyclic antidepressants (TCAs) & NE/5-HT reuptake inhibitors (SNRIs)
are nonselectively inhibit the uptake of both NE & 5-HT.
• Relatively safe even in overdose, thus they have largely replaced TCAs &
MAOIs as the drugs of choice for depression.
• SSRIs include fluoxetine (prototypic drug), citalopram, escitalopram,
fluvoxamine, paroxetine & sertraline.
Actions
• Block 5-HT reuptake increasing its concentrations in the synaptic cleft
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.
• Patients who do not respond to one antidepressant may respond to
another & about 80 % or more will respond to at least one antidepressant.
Therapeutic uses
1. Depression.
2. Others: OCD, panic disorder, GAD, posttraumatic stress disorder, social
anxiety disorder, premenstrual dysphoric disorder & bulimia nervosa (only
fluoxetine is approved for bulimia).
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Pharmacokinetics
• Food increase absorption of Sertraline which is the only SSRIs that
undergoes significant first-pass metabolism.
• Half-life of Fluoxetine is 50 hours (half-life of its active metabolite is 10
days) & of the majority SSRIs is 16-36 hours).Thus once-weekly dosing of
Fluoxetine is available.
• Fluoxetine & paroxetine are potent hepatic enzyme inhibitors, interfering
with the elimination of TCAs, antipsychotic drugs & some antiarrhythmic &
β-adrenergic antagonists.
• SSRIs dosages should be reduced in patients with hepatic impairment.
Adverse effects:
• As SSRIs have little blocking activity at muscarinic, α-adrenergic &
histaminic H1 receptors, adverse effects are fewer & less severe than that
of TCAs & MAOIs.
• May cause, anxiety & agitation, weakness & fatigue, sexual dysfunction,
weight changes, sleep disturbances (insomnia & somnolence) & the
above-mentioned potential for drug-drug interactions.
1. Sleep disturbances:
• Paroxetine & fluvoxamine are more sedating agents so, are beneficial in
patients with difficulty sleeping.
• Fluoxetine or sertraline are more activating agents so, are beneficial in
fatigued or excessive somnolence complaining patients.
2. Sexual dysfunction:
• SSRI induced sexual dysfunction (loss of libido, delayed ejaculation &
anorgasmia) can be managed by using other antidepressant with fewer
sexual side effects, such as bupropion or mirtazapine. Alternatively, the
dose may be reduced.
Use in children and teenagers:
• Due to suicidal ideation antidepressants should be used cautiously in
children & teenagers.
• Fluoxetine, sertraline & fluvoxamine are approved to treat OCD in
children & fluoxetine and escitalopram are approved to treat childhood
depression.
Overdoses:
• Compared to the TCAs cardiac arrhythmias is not usually occurred, but
citalopram may cause QT prolongation.
• Seizures (all antidepressants may lower the seizure threshold).
• Serotonin syndrome( hyperthermia, muscle rigidity, sweating, clonic
muscle twitching & mental status & vital signs changes) may occurs if
SSRIs are used in the presence of MAOI or other highly serotonergic drug.
Discontinuation syndrome:
• SSRIs abrupt withdrawal, can cause discontinuation syndrome (headache,
malaise & flu-like symptoms, agitation & irritability, nervousness & sleep
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pattern changes), the shorter acting agents & having inactive metabolites
have a higher risk for such adverse reaction.
Fluoxetine has the lowest risk of causing discontinuation syndrome.
2. Serotonin / Norepinephrine reuptake inhibitors (SNRIs)
include:
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Venlafaxine, Desvenlafaxine & Duloxetine
Inhibit the reuptake of both 5-HT & NE.
Effective when SSRIs are ineffective.
Depression is accompanied by chronic painful symptoms, such as
backache & muscle aches, against which SSRIs are also relatively
ineffective. This pain is 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,
postherpetic neuralgia, fibromyalgia, and low back pain.
Cause fewer adverse effects ( little activity at adrenergic, muscarinic, or
histamine receptors).
discontinuation syndrome may occur.
A. Venlafaxine and Desvenlafaxine
Venlafaxine
• Potent inhibitor of 5-HT reuptake & at medium to higher doses, is an
inhibitor of NE reuptake.
• high doses, is also a mild inhibitor of dopamine reuptake.
• Half-life of the parent drug & its active metabolite is about 11 hours.
Desvenlafaxine
• Active 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.
• Clinical or adverse effect are like those of venlafaxine.
B. Duloxetine
• Inhibits 5-HT & NE reuptake at all doses.
• Should not be given to patients with hepatic insufficiency..
• Side effects:
1. GI side effects include nausea, dry mouth & constipation.
2. Insomnia, dizziness, somnolence & sweating.
3. Sexual dysfunction.
4. BP or HR may increased.
5. may inhibit metabolism of antipsychotics.
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