ANTIDEPRESSANTS

MRS MUTOYA
 INTRODUCTION

• The symptoms of depression are feelings of sadness and

hopelessness, as well as the inability to experience pleasure in usual
activities, changes in sleep patterns and appetite, loss of energy, and
suicidal thoughts.
• Bipolar disorder (manic depression) involves periods of low mood
alternating with manic behaviour (excessive enthusiasm, self-
confidence, grandiose delusions, increased libido, aggression and
impatience).
 INTRODUCTION
• Depression has a close association with chronic illnesses (e.g. multiple
sclerosis, myocardial infarction, stroke, parkinson’s disease, cancer, human
immunodeficiency virus (HIV)) and untreated depression can compromise
treatment of comorbidities.
• The cause is probably multifactorial and may be precipitated by major life
events such as childbirth or bereavement.
• Genetic links are probable but no causal gene(s) have been unequivocally
identified.
 THE MONOAMINE THEORY

• The monoamine theory of depression proposes that

depression is due to a deficiency of monoamine
neurotransmitters (noradrenaline, 5-hydroxytryptamine
(5HT)) somewhere in the brain.
MECHANISM OF ACTION OF
ANTIDEPRESSANTS
 SEROTONIN-SELECTIVE REUPTAKE
INHIBITORS (SSRIS)

• E.G. Citalopram, fluoxetine, paroxetine, sertraline

• Mechanism of action
Selective inhibition of neuronal reuptake and
enhancement of synaptic concentrations of 5HT.
 CLINICAL CONTEXT

• Commonly first-line therapy for moderate to major depression.

• Take 2–4 weeks to have an effect in depression.
• Some SSRIs are also used in anxiety.
• Only fluoxetine is suitable for treatment of under-18-year-olds and,
as with other SSRIs, there is a small risk of self-harm and suicidal
thoughts.
 Adverse effects
• SSRIs have fewer side-effects than tricyclic antidepressants (tcas).
They are less dangerous in overdose than tcas or monoamine
oxidase inhibitors (MAOIs) but are still associated with
gastrointestinal disturbances (nausea), weight change (loss or gain),
rashes, sexual dysfunction, abnormal dreams and sleep disturbances.
• SSRIs may be associated with a withdrawal reaction (especially
paroxetine).
 TRICYCLIC ANTIDEPRESSANTS
• E.G. Amitriptyline, dothiepin, imipramine, lofepramine, nortriptyline,
Clomipramine
• MECHANISM OF ACTION
• Inhibition of neuronal reuptake of noradrenaline and 5HT.
• Antagonism of neurotransmitter receptors, including muscarinic, histamine and
5HT, contributes to side-effects.
 CLINICAL CONTEXT

• TCAs are generally used in depression when SSRIs

are ineffective.
• Sedating ones may be used when sleep is disturbed.
• Beneficial effects take 2–4 weeks in depression.
 ADVERSE EFFECTS

• Possess antimuscarinic activity, which causes side-effects such as dry Mouth, blurred vision,
constipation, urinary retention.
• Tcas vary in the degree of sedation caused; might be helpful for sleep disturbances or unwelcome.
• Amitriptyline and dothiepin are sedative; Imipramine, lofepramine and nortriptyline are less
sedating.
• Tcas have adverse cardiac effects, e.g. Prolonged QT interval on Electrocardiogram; increase in
catecholamines predisposes to heart block And arrhythmias. Cardiac effects (except lofepramine)
and enhancement of Alcohol effects (respiratory depression) mean that these agents are
dangerous In overdose.
• Should not be combined with other antidepressants (serious adverse Interaction).
 MONOAMINE OXIDASE INHIBITORS
• E.G. ISOCARBOXAZID, MOCLOBEMIDE, PHENELZINE, TRANYLCYPROMINE

• MECHANISM OF ACTION

• Inhibition of enzyme (MAO) that metabolises monoamines.

• CLINICAL CONTEXT

• Not widely used any more but might be worth trying in patients refractory to
other drugs.
• Moclobemide, a selective reversible inhibitor of mao-a , reduces interaction
with food. Moclobemide is relatively well tolerated with few sexual side-effects;
action reverses in 24–48 hours.
 ADVERSE EFFECTS
• MAO blockade prevents breakdown of monoamine transmitters and the indirectly acting
sympathomimetic amine, tyramine, present in the diet, e.G. In cheese, causing danger of
hypertensive crisis.

• Older MAOIs inhibit irreversibly; reactions may persist for 2–3 weeks after treatment has
stopped until new enzyme synthesised.
• Other side-effects include postural hypotension, headache, dizziness, sexual dysfunction.
• MAO-A metabolises mainly noradrenaline and 5HT; phenylethylamine is the preferred substrate
for MAO-B. Tyramine and dopamine are metabolised by both.
• To reduce side-effects and interactions, second-generation selective inhibitors of MAO have
been developed.
 SELECTIVE NORADRENALINE REUPTAKE
INHIBITORS (NARIs)

• E.G. REBOXETINE
• Limited side-effects (urinary problems, nausea, dry mouth,
constipation possible).
• Not recommended for under-18s and elderly.
 SEROTONIN/NORADRENALINE REUPTAKE
INHIBITORS (SNRIs)
• E.G. VENLAFAXINE, LEVOMILNACIPRAN, DULOXETINE, DESVENLAFAXINE

• SSRI-like action in initial 75 mg dose range. Anecdotally greater efficacy and faster
onset compared with SSRIs (unproven).
• Dose-dependent risk of increased blood pressure; contraindicated in patients with
cardiac arrhythmias or uncontrolled hypertension.
• Side-effect profile similar to SSRIs.
• Mirtazapine has a2-adrenoceptor antagonist activity. Inhibiting negative feedback by
these presynaptic receptors increases noradrenaline and 5HT transmission. Sedation
predominates in early treatment but antimuscarinic effects are limited.
 OTHER DRUGS

• LITHIUM

• Lithium (usually as lithium carbonate) is first-line therapy for the prophylaxis of bipolar
disorder.
• Lithium is toxic in overdose, so need to monitor blood levels regularly (every 3 months once
stable) to keep within narrow therapeutic window of 0.4–1 mmol/l (serum) 12 h after a dose.
Mechanism of action uncertain
• Antipsychotic drugs (haloperidol, prochlorperazine) are quick-acting and safer alternatives in
the treatment of acute manic phase.
• Carbamazepine can be used for bipolar disorder prophylaxis, particularly in patients with rapid
cycling illness (four or more episodes per year).
 ST JOHN’S WORT
• Preparations of st john’s wort (hypericum perforatum) are widely available in health
food shops, but not licensed in the UK as a medicine.
• St john’s wort inhibits reuptake of 5ht, noradrenaline and dopamine and is a weak
MAOI (properties, including side-effects, resemble first-generation antidepressants).
• There are pharmacokinetic interactions due to enzyme induction.
• Care is needed with anticonvulsants, ciclosporin, digoxin, anti-HIV drugs, oral
contraceptives, SSRIs, theophylline and warfarin.
• Active ingredients are not fully characterised and differ from preparation to preparation.
• Self-medication with unlicensed remedies can divert patients away from professional
care and should be avoided.
ATYPICAL ANTIDEPRESSANTS
END