Antidepressants
What is Depression?
The term ‘depression’ is often used to describe a range of low feelings, including sadness or low
spirits and more severe mood problems.
Symptoms include low mood, loss of interest and pleasure, reduced energy, insomnia, excessive
feelings of worthlessness and guilt, hopelessness, morbid and suicidal thoughts, poor
concentration, reduced appetite, anxiety, irritability and weight loss or weight gain.
When these symptoms are persistent and interfere with a person’s everyday life and normal
functioning, they indicate the clinical presentation of depressive disorder (also known as major
depression or clinical depression)
Mechanism of Action
Monoamine theory of
depression
Neurodevelopmental and biochemical theories propose that depression is caused by
an alteration in the level or function of monoamine neurotransmitters, especially serotonin,
dopamine and noradrenaline.
Neuroendocrine tests suggest that clinical symptoms seen in
depressed patients are due to a reduction of serotonin in the synaptic cleft, which leads
to receptor upregulation (increase in receptor numbers on the postsynaptic neuron).
https://www.newfrontierspsychiatry.com/neuroscience-of-depression-and-treatment/
Monoamine theory of depression
Treatment with antidepressants results in increased availability of serotonin within the synaptic
cleft, leading to downregulation of receptors and therefore desirable improvement in the clinical
features of depression.
An experimental technique to deplete tryptophan (an amino acid that produces serotonin and
melatonin) can reduce brain serotonin function and can induce temporary emergence of
depressive symptoms in patients vulnerable to depressive illness.
Low levels of serotonin are likely to occur with reduced dietary intake of the amino acid
tryptophan (found in foods such as chocolate, cheese, milk, yoghurt, red meat, poultry, fish,
eggs, oats, nuts and seeds).
Reserpine, a monoamine antagonist that was historically given to treat high blood pressure, is
now rarely used due to depression being a common side effect for this drug.
Other evidence in support of the monoamine hypothesis is that the levels of serotonin
metabolites measured in the CSF (cerebral spinal fluid) are significantly reduced in depression
Dopamine may also be involved in depression
Several antidepressant drugs also have dopamine agonist actions.
Antidepressants such as MAOIs (Monoamine oxidase inhibitors) inhibit the action of
monoamine oxidase (MAO) enzyme found in the synapse.
This enzyme normally breaks down monoamine neurotransmitters(serotonin, dopamine,
noradrenaline) and, therefore, antidepressant drugs that inhibit this enzyme cause increased
levels of monoamine neurotransmitters in the synaptic cleft.
DOSE AND ADMINISTRATION
a flexible approach is vital to finding the right drug for a patient, considering:
●● the nature and degree of clinical symptomatology;
●● safety in overdose;
●● previous treatment response to a drug;
●● the drug’s side effects profile, interactions with concurrent drugs and physical illness;
●● patient preference and clinical benefit in cases where there are associated co- morbid
physical and psychiatric conditions.
starting titration at lower doses is generally recommended,the doses are usually increased over
a period of days or weeks to the
Types of Anti depressants
1. Selective serotonin reuptake inhibitors
2. Serotonin- noradrenaline reuptake inhibitors
3. Tricyclic antidepressants
4. Tetracyclic (noradrenergic and specific serotonergic antidepressants)
5. Monoamine oxidase inhibitors
6. Aminoketone (bupropion)
1. Selective serotonin
reuptake inhibitors
SSRIs inhibit serotonin and noradrenaline reuptake into the presynaptic neuron.
Fewer side effects than tricyclics, do not cause sedation and are much safer in overdose
Better tolerated by older patients and are recommended as first- line treatment because SSRIs
are tolerated better by patients and are associated with lower side effects profile compared to
tricyclics.
SSRIs should be gradually stopped to avoid occurrence of discontinuation symptoms (eg
dizziness, flu like features, nausea/vomiting, fatigue, irritability, headaches, insomnia, suicide,
diarrhea, shock-like sensations), which usually occur if the drug is abruptly stopped (although
this is less so with fluoxetine).
Hyponatremia has been linked to all antidepressants and should be considered in all patients
who develop drowsiness, confusion or convulsions while taking antidepressants.
Adverse effects
Anxiety, drowsiness, insomnia, nervousness and lethargy.
Gastrointestinal symptoms (nausea, diarrhoea, bloating).
Weight loss and loss of appetite.
Sexual dysfunction in both men and women.
Tremors, sweating, headaches (less common side effects).
Antidepressants are associated with an initial worsening of anxiety and an increase of suicidal
thinking and behaviour. Monitor patient closely.
SSRIs can increase risk of falls and osteoporotic fall in people aged over 50. Monitor patients
closely and conduct blood pressure and pulse measurements if dizziness, syncope or confusion is
reported or suspected.
SSRIs
1. Citalopram
2. Escitalopram
3. Fulxoetine
4. Fluvaoxamine
5. Paroxetine
6. Sertraline
2. Serotonin- noradrenaline reuptake
inhibitors
SNRIs inhibit both serotonin and noradrenaline reuptake. Inhibition of both neurotransmitters
is essential for their antidepressant action. Venlafaxine comes in two forms, tablets
and prolonged release capsules. Venlafaxine has little or no anticholinergic (dry mouth,
constipation, blurred vision), histaminergic (sedation) or alpha- adrenergic (palpitations,
tachycardia) side effects.
SSRIs
Indications
• Major depressive disorder
• Bipolar depression
• Dysthymia
• Seasonal affective disorder
• Obsessive compulsive disorder
• Bulimia Nervosa
• Panic disorder
• Premenstrual dysphoric disorder
• Trichotilomania
• Post-traumatic stress disorder
• Social anxiety disorder
• Body dysmorphic disorder
• Substance dependence
• Smoking cessation
Adverse effects and
management
Nausea, dizziness, dry mouth, sweating, headaches.
●● In men, sexual dysfunction, failed erection, delayed ejaculation; this can continue
after drug is no longer taken.
●● In women, increased or irregular bleeding, reduced sexual desire, delayed or inability
to reach orgasm.
●● Loss of appetite.
●● Palpitations.
●● Pins and needles.
●● Raised blood pressure.
●● Sight problems.
●● Sleepiness.
SNRIs
1. Venlafaxine
2. Desvenalafaxine
3. Duloxetine
4. Levomilnacipram
3. Tricyclic antidepressants
TCAs act by blocking monoamine (noradrenaline, serotonin, dopamine) reuptake by presynaptic
neurons after neuronal discharge.
1. Reuptake blockade—These drugs block the reuptake of serotonin and norepinephrine at presynaptic
sites and increase the amount of these amines. The tertiary amines have a higher affinity for
norepinephrine, and secondary amines have a higher affinity for serotonin. TCAs also increase dopamine
transmission in frontal cortex.
2. Receptor sensitivity changes—The Tricyclic agents sensitize or upregulate postsynaptic 5-HT1A receptors.
These changes in sensitivity of the presynaptic and postsynaptic receptors occur over a period of 2 weeks,
and the onset of these changes is more consistent with the timing of antidepressant response than the
initial uptake blockade.
3. Secondary effects—The Tricyclic and Tetracyclic compounds have effects on a variety of receptors. In
particular, these drugs act on muscarinic receptors producing anticholinergic effects. They block Histamine
1 receptors producing sedation. They also block alpha 1 and alpha 2 receptors. They have effects on fast
sodium channels which explain their cardiac side effects.
Adverse effects and
management
Sedation, dry mouth, blurred vision, weight gain, constipation, sweating, movement
disorders, nightmares, increased appetite, weight gain, headache, ‘hangover effect’,
urinary retention, sexual dysfunction and lack of orgasm in women.
Cardiac complications
Patients should be offered physical health examination, eg checking blood pressure,
pulse, oxygen circulation, respiration, BMI measures, ECG and blood.
4. Tetracyclic (noradrenergic and
specific serotonergic antidepressants)
Tetracyclics are a subclass of antidepressants that include mirtazapine (Remeron) and
maprotiline (Ludiomil). They are not as widely prescribed as they were in the past, but they can
still be effective in treating severe and treatment-resistant depression.
Side effects include weight gain, drowsiness, dry mouth, and blurred vision. Quitting these
medications suddenly may also lead to withdrawal symptoms.
Tetracyclics have somewhat different primary mechanisms of action. But, to varying extents,
they increase activity in the serotonin and/or noradrenergic (norepinephrine) neurotransmitter
systems in the brain. Serotonin is thought to play a role in emotion, mood, sleep and appetite,
and norepinephrine is an important biochemical player in processes like memory and
physiological arousal
Adverse effects
Sedation, drowsiness, fatigue.
●● Increased appetite, weight gain.
●● Dry mouth and constipation.
●● Tremor, agitation, restlessness, insomnia (less common).
●● Confusion.
●● Anxiety.
●● Abnormal dreams.
●● Drop in blood pressure that occurs when moving from a lying or sitting position, or
from sitting to standing, causing dizziness or light- headedness.
●● Nausea and vomiting.
Tricyclic and Tetracyclic
Antidepressants
Indications
• Depressive disorders—It has been suggested that TCAs are more effective than
SSRIs in severe depressive episodes with melancholic features. For depressive
disorders with predominant anxiety symptoms drugs like Doxepin, Amoxapine,
and Maprotiline are more effective. Patients of depression with atypical features
are more effective. These compounds are not so useful in psychotic depression.
They are also useful in insomnia.
• Panic disorders, migraine, Enuresis, Cataplexy—Imipramine.
• Obsessive compulsive disorders, Cataplexy syndrome—Clomipramine.
• Neuropathic pain, Headache, Fibromyalgia—Amytriptiline.
• ADHD—Desipramine.
Monoamine oxidase
inhibitors
MAOIs inhibit the action of MAO enzyme, which breaks down neurotransmitters (serotonin,
noradrenaline, dopamine) in the presynaptic neuron after reuptake. By blocking the
actions of MAO enzyme, MAOIs help to increase serotonin, noradrenaline and dopamine
neurotransmission within the neuronal intracellular structures, resulting in reduction and
improvement of depressive symptoms. MAOIs are routinely used for atypical depression
and when other antidepressants have been unsuccessful. They have also been
found to be useful in patients where anxiety features persist. There are two subtypes of
MAO enzyme and they have differing substrate specificities:
1. MAO- A mainly breaks down serotonin and noradrenaline; metabolize serotonin and noradrenaline
2. whereas MAO- B breaks down dopamine ---- reduce Parkinson like symptoms
What is monoamine oxidase?
Depression is thought to be caused by low levels of the neurotransmitters dopamine, serotonin,
and norepinephrine, which collectively are called monoamines. A chemical found naturally in
the body, monoamine oxidase, removes these neurotransmitters.
By inhibiting monoamine oxidase, MAOIs allow more of these neurotransmitters to remain in
the brain, thus elevating mood through improved brain cell communication.
Monoamine oxidase is a type of enzyme that helps neurons fire throughout your body. It’s
formed in your liver and cleans up neurotransmitters in your brain once they’ve done their jobs.
Besides neurotransmitters, monoamine oxidase cleans out tyramine, a chemical that helps
regulate blood pressure. Because MAOIs inhibit monoamine oxidase from doing its job, they
adversely affect blood pressure in addition to keeping neurotransmitters at optimal levels.
People taking MAOIs have to pay special attention to their blood pressure, including avoiding
certain foods.
The monoamine receptor hypothesis of depression extends the classic monoamine
hypothesis
of depression, positing that deficient activity of monoamine neurotransmitters causes
upregulation of postsynaptic monoamine neurotransmitter receptors, and that this
leads to depression.
Mechanism of Action
Different classes of MAOIs interact in different ways with the enzyme, although all clinically used
inhibitors act at enzymes active sites and are thus at least initially competitive.
Selective MAO inhibitors act selectively to MAOA or MAOB. Reversible inhibitors help in
reducing side effects.
The MAOIs which are used to treat patients with depression are either selective inhibitors of
MAO- A (also known as reversible inhibitor of MAO- A, ie moclobemide) or non- selective MAOIs
(also known as irreversible MAOIs, ie isocarboxazid, phenelzine, tranylcypromine).
Side effects
Drug to drug interaction
Drug to food interaction (tyramine rich food )----Hypertension and stroke
Aminoketone (bupropion)
Wellbutrin is the brand name for bupropion, a type of antidepressant (aminoketone class) which
also acts as a stimulant. This drug is commonly used as a smoking cessation pharmacotherapy in
smoking cessation clinics
It is a noradrenaline and dopamine inhibitor and so increases the amount of both chemicals in
the brain
Cause weight loss
It should not be used when such weight loss might be dangerous to the patient, especially when
there is a history of an eating disorder that is not sufficiently managed, eg in patients with
anorexia or bulimia. In the UK, bupropion is currently not licensed for the treatment and
management of major depression, but it is not uncommon to find the drug used outside the
terms of its license.
Adverse effects and
management
●● Weight loss, decreased appetite.
●● Restlessness, agitation, insomnia, anxiety.
●● Constipation, dry mouth, diarrhoea.
●● Dizziness, nausea, vomiting, headache.
●● Increased libido, skin problems.
Serotonin syndrome
Serotonin syndrome is a term used to refer to a cluster of motor, autonomic and mental changes
resulting from excess serotonin neurotransmission.
Serotonin syndrome can occur when medications that cause high levels of serotonin to
accumulate in the body are administered.
It often occurs either during dose changes or when adding new drugs.
Symptoms can range from mild (shivering and diarrhoea) to severe (muscle rigidity, fever,
seizures, confusion, rapid heart rate, high blood pressure, dilated pupils, loss of muscle co-
ordination or twitching muscles)
Symptom onset is usually rapid and can occur within minutes
Serotonin syndrome
Drugs implicated in serotonin syndrome include SSRIs, SNRIs, TCAs, MAOIs, St John’s Wort and
lithium.
The risks of serotonin syndrome when taking either a SSRI or SNRI in combination with tramadol
are very serious and can be fatal if not urgently managed.
Other drugs that have been reported and can elevate serotonin levels include pethidine,
fentanyl, dextromethorphan and recreational drugs, eg cocaine, MDMA
(methylenedioxymethamphetamine) and amphetamine.
It is generally not recommended to use more than one antidepressant concomitantly as this
further increases the risk of developing serotonin syndrome.
