This document discusses drugs used in the management of affective disorders such as depression and bipolar disorder. It describes four classes of antidepressants - tricyclic antidepressants, selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, and atypical antidepressants. It also discusses mood stabilizers like lithium, carbamazepine, and valproate that are used to treat bipolar disorder. Adverse effects, mechanisms of action, drug interactions, and contraindications are described for various antidepressant and mood stabilizing drugs.

1. DRUGS USED IN THE MANAGEMENT OF
AFFECTIVE DISORDERS
NEUROPHARMACOLOGY
[DR S. N. KANYIMBA]
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2. Introduction
Affective disorders are a group of psychoses associated with changes of
mood:
• Unipolar depression
• Bipolar disorder (manic-depressive illness)
Antidepressants
Drugs used in the treatment of unipolar depressive episodes and
depressive phase in bipolar disorder are classified into four groups:
1. Tricyclic antidepressants (TCAs)
2. Selective serotonin reuptake inhibitors (SSRIs)
3. Monoamine oxidase inhibitors (MAOIs)
4. Atypical antidepressants
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3. Antidepressant drugs …. cont’d
Antidepressant therapeutic efficacy occurs after 2 – 4 weeks of
drug administration and is closely associated with
• Decreased cyclic AMP
• Reduction (down-regulation) of post-synaptic beta-
adrenoceptors
• Increased responsiveness of post-synaptic serotonin 5-HT1A
receptors
• Desensitization of presynaptic noradrenaline and serotonin
autoreceptors
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4. Antidepressant drugs …. cont’d
• All antidepressants have similar therapeutic efficacy,
although individual patients may respond better to one
drug than another
• All antidepressants have delayed therapeutic efficacy –
effects are seen after 2-4 weeks
• Selection is often based on patient co-morbidities,
associated adverse effects, drug interactions, drug-food
interactions, contra-indications and patient preference
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5. Tricyclic antidepressants and related drugs
• Examples: amitriptyline, imipramine, nortriptyline, desipramine,
dosulepin (dothiepine), lofepramine
• MOA: block uptake of noradrenaline and 5-HT into the presynaptic
terminal (inhibit the re-uptake pumps)
• Therapeutic effects take 2-3 weeks to develop
• TCAs also block muscarinic, histamine H1 and alpha-adrenergic
receptors (this contributes to their unwanted effects)
• Adverse effects: dry mouth, blurred vision, constipation, postural
hypotension, increased risk of arrhythmias, sedation, weight gain
• Overdose: arrhythmias, shock, respiratory depression, seizures,
coma and death (have a narrow therapeutic index)
• Contraindications: arrhythmias, recent myocardial infarction, manic
phase, severe liver disease, seizure disorders, and patients taking
lignocaine, anticholinergic drugs or alcohol
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6. Selective serotonin reuptake inhibitors
• Examples: flouxetine, fluvoxamine, citalopram, paroxetine and
sertraline
• MOA: selectively inhibit the reuptake of serotonin into
presynaptic nerve terminals
• Similar efficacy to TCAs
• They are better tolerated than TCAs and MAO inhibitors, and
are safer in overdose
• Preferred in elderly patients because of low anti-muscarinic
effects
• Adverse effects: headache, nausea, vomiting, diarrhoea,
insomnia, anxiety, agitation, sexual dysfunction. May induce
suicidal ideation in children, adolescents and young adults.
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7. Mono-amine oxidase inhibitors
• Examples: phenelzine, tranylcypromine, isocarboxazide and
moclobemide
• MOA: inhibits monoamine oxidase (MAO), the enzyme that
metabolizes monoamines (noradrenaline, serotonin and dopamine).
Inhibition of MAO-A which preferentially degrades norepinephrine
and serotonin is responsible for the therapeutic efficacy of MAOIs
(MAO-B degrades dopamine preferentially). Moclobemide is selective
for MAO-A.
• Adverse effects: headache, CNS excitement, tremors, postural
hypotension, dry mouth, blurred vision, sexual dysfunction
(phenelzine), weight gain and sleep disturbances
• Overdose: agitation, hyperthermia, seizures, hypotension or
hypertension
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8. MAOIs …. cont’d
Drug and food interactions
• They inhibit the metabolism of indirectly acting sympathomimetic drugs
(e.g. phenylephrine, ephedrine and pseudoephedrine) and with tyramine
from certain foods such as cheese, mature wines, yeast, fish, sausages)
resulting in headache, arrhythmias and severe hypertension. These effects
are due to the release of increased stores of catecholamines resulting
from increased levels of the drugs.
• Interact with SSRIs, TCAs and pethidine resulting in the “serotonin
syndrome” (characterised by tremor, hyperthermia, muscle rigidity and
cardiovascular collapse)
• MAOIs result in additive sedation and CNS depression in the presence of
barbiturates, ethanol and opioids
Indications
• Used for depression refractory to other antidepressants
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9. Miscellaneous anti-depressant drugs
• Venlafaxine: inhibits reuptake of noradrenaline and serotonin.
Adverse effects include nausea, dizziness, sexual disturbances,
anxiety and insomnia. Useful in patients not responding to other
anti-depressants.
• Reboxetine: selectively inhibits reuptake of noradrenaline
• Trazodone: serotonin reuptake inhibitor. Adverse effects: postural
hypotension and priapism. Safer than TCAs in overdose.
• Nefazodone: blocks serotonin reuptake. Causes sedation and mild
postural hypotension. Used in the prophylaxis of recurrent
depression.
• Mirtazapine: blocks alpha2-adrenoceptors thereby increasing
noradrenaline release. Is very sedative and causes weight gain.
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10. Treatment of bipolar disorder
Bipolar disorder is treated with a combination of mood stabilizers and
antidepressants, and sometimes antipsychotics (anti-psychotics are
given during the manic phase)
Mood stabilizers prevent mood swings that are seen in bipolar disorder
Mood stabilizers include: lithium, carbamazepine, valproate,
lamotrigine and gabapentin
Carbamazepine
Effective in prophylaxis of bipolar disorder and treatment of acute
mania
Can be combined with lithium for better therapeutic effects
Valproate
Can be used as monotherapy in mild to moderate cases and in
combination with lithium in refractory cases
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11. Lithium
• Has anti-manic and anti-depressant activity
• It is a mood stabilizer and suppresses acute mania
• MOA: inhibits inositol monophosphate, thereby decreasing the activity
of the second messengers diacylglycerol and inositol-1,4,5-
triphosphate
• Uses: (1) prophylaxis and treatment of bipolar disorder (2) prophylaxis
and treatment of acute mania (3) prophylaxis of resistant recurrent
depression
• Adverse effects: lithium has a narrow therapeutic window and adverse
effects are common. They include thirst, nausea, vomiting, diarrhoea,
tremor and polyuria. Late adverse effects include weight gain, oedema,
acne, nephrogenic diabetes insipidus and hypothyroidism.
• High plasma concentrations cause drowsiness, confusion, ataxia,
blurred vision, nystagmus and seizures
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12. Lithium …. cont’d
• Over-dosage: delirium, muscle twitching, convulsions,
arrhythmias and renal failure and death
• Plasma concentration monitoring is essential to avoid toxicity
• Contraindications: antipsychotics, NSAIDs, diuretics,
pregnancy, breastfeeding
• Diuretics deplete sodium and this depletion results in
increased renal reabsorption of lithium thereby increasing
lithium toxicity
• NSAIDs decrease the renal clearance of lithium resulting in
increased risk of toxicity
• Treatment of lithium toxicity: discontinue lithium
administration, haemodialysis and anti-convulsants
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13. ENDE
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