Pharmacology-2, 2023-2024, Prof. Dr.
Marwa Safar
DRUGS USED IN TREATMENT OF AFFECTIVE DISORDERS
(MOOD DISORDERS)
Learning Objectives:
• Demonstrate understanding of the pathophysiology of depression
and mania.
• Classify antidepressants according to their mechanism of action.
• Enumerate clinical uses of antidepressants.
• Compare side effects of various antidepressants.
The affective disorders include depression & mania.
1. Uni-polar depression → patient is always in depressed mood; most common.
➢ Signs of depression: Emotional symptoms: sadness, hopelessness,
frustration, feeling of low self-esteem, apathy, and loss of motivation and interest
in usual activities (anhedonia),
Biological symptoms (psychosomatic): loss of libido, sleep disturbances,
anorexia, chronic pain, and suicidal thoughts.
2. Bipolar depression (manic depressive illness) → it is characterized by occurring
episodes of elevated & depressed mood.
➢ Signs of mania: enthusiasm, self-confidence, rapid thought and speech
patterns (non-stop talk), impaired judgment.
Pathophysiology of Depression “Biogenic amine theory; monoamine theory of mental
depression”
Depression is due to of monoamines especially NE and/or 5-HT in brain, whereas
mania is due to monoamines in brain.
expression of brain receptors 5HT2A, 5HT2C
Neurotrophic and cytokines theory: brain neurotrophic factor (BDNF), hypothalamus-
pituitary axis dysregulation, proinflammatory cytokines e.g: IL-1; IL-6; TNF-α
Genetic (endogenous; major depressive disorder MDD; may not be associated with easily
recognized causes) and social factors (exogenous or reactive depression) are involved.
Episodes of MDD may occur at intervals throughout one’s lifetime.
ANTIDEPRESSANT DRUGS
Treatment goal = NA and /or 5-HT in brain.
Typical antidepressants: NA and /or 5-HT in brain.
Atypical antidepressants: work by other mechanisms.
Pharmacology-2, 2023-2024, Prof. Dr. Marwa Safar
1. MONOAMINE OXIDASE INHIBITORS (MAOIs)
➢ Non-selective irreversible MAO inhibitors (blocks MAOA& MAOB)
(Phenelzine, Isocarboxazid, Tranylcypromine=Amphetamine like).
➢ Selective reversible MAOA inhibitors: Moclobemide
➢ Selective MAOB inhibitors: Selegiline
MOA:
MAOIs inactivate MAO (reversible or irreversible) metabolism of NA, 5-HT
→ NA & 5-HT leakage of greater amounts into synaptic space → activation
of NE and 5-HT receptors → antidepressant effect.
N.B. Their antidepressant effect is delayed for 2 week or more, and it persists for 2-3
weeks after stopping the drug [time taken for regeneration of a new enzyme].
Contraindications and precautions on use:
➢ MAOIs should not be taken with indirect acting sympathomimetics
including tyramine that is present in aged cheese, yeast products, smoked fish,
herring, chicken liver and red wine Why??
Tyramine is Metabolized by MAO in gut and liver, if not degraded blood
pressure
MAOIs → NE release → blood pressure
Tyramine + MAOIs → NE level + tyraminehypertensive crisis
➢ Symptoms of hypertensive crisis: occipital headache, stiff neck, tachycardia, nausea,
hypertension, cardiac arrhythmias, excitation, seizures
➢ Management of hypertensive crisis: −blockers e.g. phentolamine
➢ Certain sympathetic drugs used in the treatment of cold symptoms (decongestants)
interact with MAO inhibitors causing the potentiation of the effect of sympathetic agents.
Uses: Last line antidepressants in unresponsive patients
The use of MAOI is now limited due to dietary restrictions.
2. TRICYCLIC ANTI DEPRESSANTS (TCAs); named after
their 3 ringed structure
Amitriptyline, Clomipramine, Nortriptyline, Protriptyline, Imipramine,
Desipramine, Doxepin
MOA
1. TCAs inhibit the neuronal re-uptake of NE and 5-HT→ NE and 5-HT in the .1
Brain synapes→ antidepressant action (elevates mood). Effect is delayed for 2-3
weeks. maximum benefit may require up to 12 weeks or more.
2. Muscarinic antagonists, Have strong Anticholinergic activity “Strong Atropine
actions”.
3. H1-blocker “Anti-histaminic” Sedative.
4. α1 blocker
Pharmacology-2, 2023-2024, Prof. Dr. Marwa Safar
USES
1. Depression
2. Nocturnal enuresis
(especially IMIPRAMINE due to Anticholinergic=Atropine like actions).
3. Certain phobic states.
4. Severe chronic pain as diabetic peripheral neuropathy, trigeminal neuralgia,
fibromyalgia.
5. Attention deficit hyperactive disorder in children (ADHD).
6. Insomnia.
Adverse effects:
1. Anticholinergic (Atropine) adverse effects; dry mouth, constipation,
urine retention (C.I. in Prostatic patients), tachycardia, blurred vision,
aggravating glaucoma, ..etc.
2. Sedation due to H1 blocking activity (given at night)
3. Orthostatic (postural) hypotension and reflex tachycardia due to 1 blocking
activity.
4. Weight gain.
Overdose: 3Cs: Coma (excessive sedation), Convulsions, Cardiac
arrhythmias (tachycardia; wide QRS; long QT interval)
N.B. Because depressed patients might attempt suicide, the safety of an antidepressant in overdose is
an important consideration when selecting a drug for a particular patient.
Treatment of Adverse Effects: arrhythmia can be treated by the intravenous
administration of sodium bicarbonate. Sodium bicarbonate increases the ratio of
nonionized TCA to ionized TCA and thereby decreases the binding to the sodium
channel in cardiac membranes.
Why hemodialysis is not indicated in case of overdose? Due to large volume of distribution
(drug mainly in tissues not blood)
Drug interactions:
1. TCAs + MAOIs → Potentiation → Hypertension crisis= CNS, hypertension,
hyperpyrexia ( temp), convulsions, coma.
2. TCAs + Alcohol (Ethanol) & other CNS depressants→ toxic sedation.
3. TCAs U1 (uptake I= neuronal uptake) uptake of indirect Sympathomimetics
as Amphetamine effect
4. TCAs effect of Direct Sympathomimetics
N.B.
1. Tolerance to the Anticholinergic properties and autonomic effects of the TCAs
develops within a short time BUT NO tolerance to the antidepressant effect.
2. Therapeutic index: narrow, Monitoring is essential
Pharmacology-2, 2023-2024, Prof. Dr. Marwa Safar
3. SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs)
Fluoxetine [prototype], Paroxetine, Sertraline, Fluvoxamine, Citalopram,
Escitalopram (S-enantiomer of citalopram)
MOA:
SSRIs U1 of 5-HT only selectively inhibit the neuronal reuptake of 5-HT → 5-
HT level in the synapse → antidepressant effect after 2-3 weeks, maximum benefit
may require up to 12 weeks or more.
Weak Atropine actions → less side effects than TCAs.
Clinical uses:
1. Depression (Expensive drugs opposite to TCAs), preferred therapy nowadays
2. Generalized anxiety disorder (GAD).
3. Eating disorders “Bulimia nervosa and anorexia nervosa”.
4. Premenstrual dysphoric disorder (PMDD).
5. Panic disorders.
6. Obsessive compulsive disorder (OCD).
7. Posttraumatic stress disorder (PTSD).
Adverse effects:
1. Gastrointestinal side effects (nausea, diarrhea), take after food.
2. Agitation & Insomnia (given at day time)
3. Sexual dysfunction.
4. Changes in weight
N.B. No cardiac arrhythmia (c.f. TCAs).
Advantages over TCAs:
NO anticholinergic side effects, NO sedation, NO weight gain.
Dapoxetine
Drug interactions:
1. Most SSRIs inhibit HME (hepatic microsomal enzymes=CytP450) activity of
drugs that are metabolized by CytP450 Toxicity e.g. TCAs, -blockers.
2. SSRIs (inhibit reuptake of 5-HT) + MAOIs (inhibit destruction of 5-HT) 5-HT
life threatening serotonin syndrome (agitation, restlessness, confusion, insomnia,
hypertension, and gastrointestinal symptoms and if severe may cause hyperthermia,
muscle rigidity, sweating, seizures and changes in mental status and vital signs). Both
types of drugs require at least 2 weeks washout period before the other type starts.
N.B. Serotonin syndrome also occurs due to over dose of SSRIs.
Discontinuation syndrome: Occurs after abrupt withdrawal, Symptoms: headache,
malaise, and flu-like symptoms, agitation and irritability, nervousness, and changes in
sleep pattern.
Pharmacology-2, 2023-2024, Prof. Dr. Marwa Safar
4. Serotonin/Norepinephrine reuptake inhibitors (SNRIs)
Venlafaxine, Desvenlafaxine (demethylated venlafaxine; active metabolite of
venlafaxine), Duloxetine, Milnacipran, Levomilnacipran
MOA: inhibit the reuptake of both 5-HT and NE.
• SNRIs, unlike the TCAs, have little activity at α, M, H receptors → adverse effects
than the TCAs.
Uses:
1- Depression in patients in whom SSRIs are ineffective.
2- Chronic painful symptoms accompanying depression (e.g. backache and muscle
aches). This pain is modulated by both 5-HT and NE pathways therefore SSRIs are
relatively ineffective
3- Chronic neuropathic pain (diabetic peripheral neuropathy, fibromyalgia, low back pain).
4- Generalized anxiety disorder.
• May precipitate a discontinuation syndrome if abruptly stopped.
ATYPICAL ANTIDEPRESSANTS
Mixed group of agents that have actions at several different sites
5. Serotonin Receptor Antagonists
Nefazodone, Trazodone
Mirtazepine
- Block the 5-HT2A receptor, a G-protein coupled receptor located in several brain
regions. It is believed that post-synaptic 5-HT2A overdensity is involved in the
pathogenesis of depression.
- Mirtazapine blocks presynaptic 2 autooceptor (responsible for negative feedback of
transmission release)→ NE & 5HT release
- Nefazodone, Trazodone block 1 receptor → postural hypotension
- They are sedatives, because of their potent histamine H1-blocking activity (Useful in
depressed patients having difficulty sleeping).
- Uses: Antianxiety, antidepressant.
Side effects: Sedation, dizziness, gastrointestinal disturbances, increased appetite, and
weight gain.
Nefazodone is hepatotoxic therefore was withdrawn from some countries.
Trazodone causes priapism (sustained and painful erection in males).
6. Vortioxetine
❑ Vortioxetine increases serotonin concentrations in the brain → utilizes a
combination of serotonin reuptake inhibition, 5-HT1a agonism, and 5-HT3 and 5-
HT7 antagonism as its suggested mechanisms of action to treat depression.
❑ The common adverse effects include nausea, constipation, and sexual dysfunction
(serotonergic mechanisms)
Pharmacology-2, 2023-2024, Prof. Dr. Marwa Safar
7. Bupropion
• Norepinephrine and dopamine reuptake inhibitor (NDRI).
• Nicotinic receptor antagonist.
• Useful for decreasing cravings and attenuating withdrawal symptoms of nicotine in
patients trying to quit smoking.
Remember: Varenicline is a partial agonist of nicotinic receptors used in smoking cessation.
• Useful in treatment of bipolar depression and ADHD.
• Very low incidence of sexual dysfunction.
Extracts of the plant St. John’s wort (Hypericum perforatum)
The extracts contain a substance called hypericin and several flavones.
Some of these compounds inhibit MAO, whereas others appear to block the neuronal
reuptake of serotonin.
Hypericum extracts appear to cause fewer adverse effects than other antidepressants
but are not as effective as prescription antidepressants.
Electroconvulsive therapy (ECT) is a successful physical tool to treat depression
that usually acts more rapidly than drugs, and can be used in combination with drugs.
N.B.
All antidepressant are with delayed onset (2-4 weeks), although their effect on NA, 5-
HT level doesn’t require such a long time this suggest 2ry effects in brain that may be
involved in their antidepressant.
Treatment of Mania and Bipolar Manic Depression
Mood stabilizer
1. Lithium
It remains the drug of choice (DOC) for bipolar disorders. Usually
antidepressants/antipyschotics/sedatives are required to be taken with lithium.
MOA: Still Unknown
i. Lithium decreases central cAMP, IP3 formation (2nd messengers)→
neuronal response to serotonin and NE.
ii. Lithium is a monovalent cation that mimics the role of Na+ in the excitable
tissue. It can enter the neuron through the Na+ channel but unlike Na+ it is not
pumped out by Na+/K+ ATPase pump partial loss of intracellular K+
Conc. gradient of K+ form inside to outside K+ efflux excitation of
neurons partial depolarization & in excitability of nerve tissue.
N.B.
Narrow therapeutic index so monitoring is essential.
Pharmacology-2, 2023-2024, Prof. Dr. Marwa Safar
Side effects:
Polyuira, polydepsia, polyphagia (Diabetes insipidus, it interferes with the action of antidiuretic
hormone and thereby inhibits the kidney’s ability to concentrate the urine; manage with amiloride), fine
hand tremors (can usually be controlled by β-adrenoceptor antagonist), thyroid function (blocking
thyroid hormone synthesis and release).
Lithium is renally eliminated, and should be used cautiously in renally impaired patients.
Teratogenicity: Ebstein’s anomaly (malformed tricuspid valve)
2. Some antiepileptic drugs e.g. carbamazepine, valproic acid, lamotrigine.
3. Some antipsychotics e.g. chlorpromazine, haloperidol, risperidone, olanzapine,
ziprasidone, aripiprazole, quetiapine
Some video links:
Pathophysiology of Depression
https://www.youtube.com/watch?v=QEjWLj5wAFM
Unipolar depression
https://www.youtube.com/watch?v=tvpVfXAC5Ow
Bipolar disorder
https://www.youtube.com/watch?v=RrWBhVlD1H8
ANTIDEPRESSANT DRUGS “SSRI” mechanism of action
https://www.youtube.com/watch?v=T25jvLC6X0w
ANTIDEPRESSANT DRUGS - SSRIs, SNRIs, TCAs, MAOIs, Lithium
https://www.youtube.com/watch?v=-EMg12QBUx4
Fluoxetine as SSRI
https://www.youtube.com/watch?v=kKDXqlSWovA
SNRIs mechanism of action
https://www.youtube.com/watch?v=l3N8ThFbBvs
Serotonin
https://www.youtube.com/watch?v=4D3IlIcqny4
Atypical antidepressants
https://www.youtube.com/watch?v=zfTNPKrnfTE
Trade names for antidepressant drugs
https://www.youtube.com/watch?v=JDaYDWEc15k
