19. Antidepressants

Last updated on December 7, 2019 at 18:21

Depression

Depression is a common mental illness. It’s a major cause of disability and premature death. There is an increased risk for suicide, and people suffering from depression have increased risk to die of other causes as well.

We can distinguish multiple types of depression:

  • Reactive depression
  • Endogenous depression
  • Manic depression or bipolar disorder

Reactive depression is that which occurs after stressful life events. This type is the most common. Endogenous depression shows a familial pattern. Bipolar disorder is characterised by alternating depression and mania.

Clinical features:

  • Low mood
  • Apathy
  • Anhedonia (reduced feeling of pleasure)
  • Loss of motivation
  • Feeling of guilt

Pathomechanism:

According to the monoamine theory depression is caused by a deficit of monoamine transmitters in the brain, including noradrenaline and serotonin. The theory is supported by how drugs that increase monoamine transmission in the CNS improves symptoms of depression, while drugs that decrease monoamine transmission (like reserpine) worsens symptoms.

However, this theory fails to explain how antidepressant drugs rapidly increases the monoamine transmission in the brain, but the antidepressant effect comes only many weeks later. We actually don’t know much about the mechanism behind depression.

Treatment:

All antidepressants work by increasing noradrenergic and/or serotoninergic transmission in the CNS. The most important ones are the SSRIs and SNRIs, which are used for long-term treatment of depressive conditions and many other conditions. Benzodiazepines are used for treatment of acute symptoms.

Only around 1/3 of patients will achieve remission after treatment with their first antidepressant. Often patients must try different drugs and different combinations to find something that works for them. Treatment is maintained for 6 months minimum to prevent relapse.

Selective serotonin reuptake inhibitors

Selective serotonin reuptake inhibitors (SSRIs) are first-line drugs in many conditions. They work by enhancing serotoninergic transmission in the CNS.

SSRIs take about 1 – 2 months to reach maximum effect and are therefore not used for treatment of acute symptoms but rather for long-term maintenance therapy.

The important drugs here are fluoxetine, paroxetine, sertraline and escitalopram. The best SSRI for depressive symptoms is escitalopram, while the best one for anxiety is paroxetine.

Indications:

  • Major depressive disorder
    • SSRIs (and SNRIs) are first-line drugs in the treatment of MDD
  • Anxiety disorders
    • Generalized anxiety disorder
    • PTSD
    • Panic disorder
    • OCD
  • Bulimia nervosa
  • Social anxiety disorder

Mechanism of action:

These drugs inhibit the serotonin transporter (SERT), a protein that reuptakes serotonin in the synaptic cleft. By inhibiting this transporter SSRIs increase the concentration of serotonin in the synapse.

Pharmacokinetics:

These drugs have significant first pass metabolism. They’re also lipid soluble and therefore have a very large volume of distribution (VD) of around 5 – 50 L/kg.

Side effects:

  • Syndrome of inappropriate ADH
  • Sexual dysfunction
    • Diminished libido
    • Anorgasmia
  • Weight gain
  • Drowsiness
  • Insomnia
  • Serotonin syndrome
    • Especially if combined with MAO inhibitors or tricyclic antidepressants

Serotonin syndrome is caused by too much serotoninergic activity in the CNS. It is similar to neuroleptic malignant syndrome (NMS) in that both cause hyperthermia and hypertension. In NMS rigidity is expected while in serotonin syndrome clonus is expected instead. Cyproheptadine, a 5-HT2 antagonist can treat serotonin syndrome.

Serotonin norepinephrine reuptake inhibitors

Serotonin norepinephrine reuptake inhibitors (SNRIs) are also first-line drugs in many conditions. They also work by enhancing serotoninergic transmission in the CNS. Unlike SSRIs these drugs inhibit the reuptake of both norepinephrine and serotonin.

Like SSRIs these drugs take 1 – 2 months to reach maximal effect and are therefore not used for treatment of acute symptoms.

The important drugs here are venlafaxine and duloxetine.

Indications:

  • Major depressive disorder
  • Anxiety disorders
    • Generalized anxiety disorder
    • PTSD
    • Panic disorder
    • OCD
  • Pain disorders
    • Diabetic neuropathy
    • Neuropathic pain
    • Chronic pain
    • Fibromyalgia

Mechanism of action:

These drugs inhibit the reuptake of serotonin and norepinephrine by inhibiting serotonin transporter (SERT), and norepinephrine transporter (NET)/uptake-1. By inhibiting these transporters these drugs increase the availability of serotonin and norepinephrine in the synaptic cleft.

Pharmacokinetics:

These drugs have significant first pass metabolism. They’re also lipid soluble and therefore have a very large volume of distribution (VD) of around 5 – 50 L/kg.

Side effects:

  • Hypertension
  • Insomnia
  • Agitation
  • Serotonin syndrome

Withdrawal:

Withdrawal of SSRIs (and SNRIs) causes flu-like symptoms that last for 1 – 2 days.

Tricyclic antidepressants

Tricyclic antidepressants (TCAs) are old drugs that are now third line treatments of depressions. This is because their overdose can be lethal, they have multiple drug interactions and cause numerous adverse effects.

Their name comes from their chemical structure which involves three rings.

The important drugs here are amitriptyline, nortriptyline and protriptyline.

Indications:

  • Depression
    • As third-line
  • Pain disorders
    • Diabetic neuropathy
  • Migraine prevention – especially amitriptyline
  • OCD – especially clomipramine

Mechanism of action:

These drugs inhibit the reuptake of serotonin and norepinephrine by inhibiting serotonin transporter (SERT), and norepinephrine transporter (NET). By inhibiting these transporters these drugs increase the availability of serotonin and norepinephrine in the synaptic cleft.

They are very “dirty” drugs so they also block muscarinic receptors, histamine H1 receptors, α1 adrenergic receptors and myocardial sodium channels.

Side effects:

  • Sexual dysfunction
    • Reduced libido
    • Anorgasmia
  • Due to blocking of muscarinic receptors
    • Dry mouth
    • Constipation
  • Due to blocking of histamine receptors
    • Sedation
    • Weight gain
  • Due to blocking of α1 adrenergic receptors
    • Orthostatic hypotension
  • Due to blocking of myocardial sodium channels
    • Arrhythmias
    • Decreased contractility
    • Widened QRS complex
    • Prolonged QT interval
  • Seizures
  • Serotonin syndrome
Monoamine oxidase inhibitors

These drugs, also called MAO-A inhibitors, are one of the first antidepressant drugs that were invented. Nowadays they’re only used to treat depression that doesn’t respond to any other treatment, because they cause severe adverse effects and drug and food interactions.

The important drug here is moclobemide.

Indications:

  • Depression
    • As a third-line drug

Mechanism of action:

MAO inhibitors irreversibly inhibit monoamine oxidase type A, the enzyme that inactivates monoamine neurotransmitters. This increases the level of monoamine neurotransmitters like serotonin and norepinephrine in the CNS.

Side effects:

  • Orthostatic hypotension
  • Sexual dysfunction
  • Weight gain
  • Serotonin syndrome
  • Cheese reaction
    • Hypertension
    • Sweating
    • Stroke
    • Myocardial infarction

The “cheese reaction” occurs when a person taking MAO inhibitors eats food containing tyramine, like aged meats and cheese. Tyramine in foods is usually metabolised by MAO-A in the GI tract mucosa before it reaches the circulation. In people who take MAO inhibitors however, tyramine will enter the circulation. Here it causes norepinephrine to be released, causing sympathetic activation involving malignant hypertension and sweating. This reaction can be so strong that a stroke or myocardial infarction occurs.

Contraindications:

MAO inhibitors should not be combined with other drugs that increase serotonin transmission like SSRIs and SNRIs as serotonin syndrome can occur.

Atypical antidepressants

These antidepressants don’t fit in any of the other groups. These include bupropion, mirtazapine and trazodone.

Indications:

Bupropion

  • Depression
  • Smoking cessation

Mirtazapine

  • Depression
    • Especially depression accompanied by insomnia
    • Especially if weight gain is desired

Trazodone

  • Depression
    • Especially depression accompanied by insomnia

Mechanism of action:

Bupropion inhibits the reuptake of norepinephrine and dopamine. Its structure resembles that of amphetamines, which also gives it a CNS stimulatory effect.

Mirtazapine inhibits presynaptic α2 adrenergic receptors, which increases norepinephrine and serotonin release from the presynaptic membrane. It also inhibits 5-HT2 and 5-HT3 serotonin receptors and histamine H1 receptors.

Trazodone inhibits postsynaptic 5-HT2 serotonin receptors and the reuptake of serotonin. It also inhibits α1 adrenergic receptors and H1 histamine receptors.

Side effects:

Bupropion

  • Seizures
    • Especially in bulimic and anorexic patients
  • No sexual dysfunction
  • No weight gain

Mirtazapine

  • Due to blocking of histamine receptors
    • Sedation
  • Weight gain
  • No sexual dysfunction

Trazodone

  • Due to blocking of α1 receptors
    • Priapism (persistent erection for more than 4 hours)
    • Orthostatic hypotension
  • Due to blocking of H1 histamine receptors
    • Sedation
  • Sexual dysfunction
  • Serotonin syndrome
St. John’s wort

St. John’s wort is a plant that has some antidepressant effect. It inhibits norepinephrine and serotonin reuptake.

It’s an inducer of CYP3A4 and CYP1A2 and therefore alters the effect of drugs that are biotransformed by one of these enzymes. It should therefore not be combined with any of these drugs.

Mood stabilizers

Mood stabilizers are used to treat bipolar disorder. This condition is characterised by alternation of manic and depressive phases. A manic phase consisting of irritable mood, while a depressive phase consists of typical symptoms of depression.

The only important drug here is lithium.

Indication:

Bipolar disorder.

Mechanism of action:

The exact mechanism of action is not known, but lithium interferes with the protein kinase C (PKC) pathway.

Toxicity:

Lithium has a very narrow therapeutic window, so its level in the blood must be monitored often.

Side effects:

  • GI symptoms
    • Mostly seen in acute lithium toxicity
    • Nausea
    • Vomiting
  • Neurologic symptoms
    • Mostly seen in chronic lithium toxicity
    • Tremor
    • Confusion
    • Ataxia
  • Reversible hypothyroidism
  • Nephrogenic diabetes insipidus
  • Congenital malformations in the heart

Pharmacokinetics:

Lithium is just a small cation, so no biotransformation can be performed on it. Instead it’s excreted unchanged by the kidneys.

Interactions:

Any drug that decreases the GFR, like thiazide diuretics or NSAIDs, will decrease the clearance of lithium.


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18. Antipsychotic drugs

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20. General anesthetics

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