Page created on June 10, 2019. Last updated on January 7, 2022 at 22:25

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.

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.

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 antidepressant effect of the SSRIs is similar, but their efficacy at treating other conditions may vary.

Compounds

• Escitalopram (Cipralex®)
• Citalopram
• Fluoxetine
• Fluvoxamine
• Paroxetine
• Sertraline

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

The first choice for depressive symptoms is usually escitalopram, while the best one for anxiety is paroxetine.

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 (not important)

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

Side effects

• Sexual dysfunction
  • Diminished libido
  • Anorgasmia
• Increased risk for suicide
• Weight gain
• Drowsiness
• Insomnia
• Syndrome of inappropriate ADH
• Serotonin syndrome

In the first weeks after beginning treatment, there is a paradoxical increased risk for suicide. It’s important to screen for suicidal behaviour and be mindful of this.

Side effects usually disappear or improve over time.

Serotonin syndrome is a potentially life-threatening condition caused by too much serotoninergic activity in the CNS, and never occurs on SSRIs alone but may occur when SSRIs are combined with other serotoninergic drugs, like MAO inhibitors or TCAs. It is similar to neuroleptic malignant syndrome (NMS) in that both cause hyperthermia and altered mental status. However, in NMS rigidity is expected while in serotonin syndrome clonus is expected instead. Cyproheptadine (a 5-HT₂ antagonist) treats serotonin syndrome.

Withdrawal

Sudden withdrawal of SSRIs and SNRIs causes flu-like symptoms, dizziness, headache, irritability, etc., that last for 1 – 2 days. Slow tapering avoids these symptoms.

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.

Compounds

• Venlafaxine
• Desvenlafaxine
• Duloxetine

Indications

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

In addition to psychiatric disorders, SNRIs are effective in the treatment of pain disorders, including neuropathic pain.

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 (not important)

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

Side effects

• Hypertension
• Insomnia
• Agitation
• Serotonin syndrome

Withdrawal

Sudden withdrawal of SSRIs and SNRIs causes flu-like symptoms, dizziness, headache, irritability, etc., that last for 1 – 2 days. Slow tapering avoids these symptoms.

Tricyclic antidepressants

Tricyclic antidepressants (TCAs) are old drugs that are now third line treatments of depression. This is because their overdose can be lethal, they have multiple drug interactions and cause numerous adverse effects. However, they are effective drugs in treating other conditions, such as migraine and neuropathic pain.

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

Compounds

• Amitriptyline (Sarotex®)
• Nortriptyline
• Imipramine
• Clomipramine
• Doxepin

Amitriptyline is the most frequently used.

Indications

• Depression (as third-line)
• Neuropathic pain disorders
• 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 as they also block muscarinic receptors, histamine H1 receptors, α1 adrenergic receptors and myocardial sodium channels.

Side effects

These drugs have a high side effect profile with significant side effects, although rarely severe.

• 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.

Compounds

• Moclobemide

The only drug here is moclobemide.

Indications

• Depression (as third-line)

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.

Compounds

• Bupropion (Wellbutrin®)
• Mirtazapine (Remeron®)
• Trazodone

Indications

Bupropion also has a stimulatory and amphetamine-like effect, and may be used for depression if this is desired. It’s also used for smoking cessation when used alone, or as an appetite suppressant when combined with naltrexone. It also notably doesn’t cause sexual dysfunction, making it an appealing choice for those with depression who developed this side effect on SSRIs.

Mirtazapine also has a sedative and hypnotic effect, and may be used for depression if this is desired, for example if insomnia is an issue. It also has an appetite-increasing effect, which may be beneficial in some cases.

Trazodone also has a sedative and hypnotic effect, and may be used for the same indications as mirtazapine.

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

Mood stabilizers

Mood stabilizers are used in bipolar disorder. The only drug which is exclusively a mood stabiliser is lithium, and that’s what will be discussed here. However, multiple other drugs from other classes are used as mood stabilisers as well.

Compounds

• Lithium
• Antiepileptics
  • Carbamazepine
  • Lamotrigine
  • Valproate
• Antipsychotics
  • Quetiapine
  • Olanzapine

Indication

• Maintainance treatment of bipolar disorder, to prevent recurrence of mania
• Acute treatment of mania

Mechanism of action

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

Dosage

Lithium has a very narrow therapeutic window, so its level in the serum must be monitored often and the dose adjusted accordingly. In the acute setting the serum level should be monitored daily, while in the chronic setting it may be monitored weekly/monthly.

It’s given orally, and the target serum concentration is 0,6 – 1,2 mmol/L.

Side effects

• GI symptoms
  • Mostly seen in acute lithium toxicity
  • Nausea
  • Vomiting
• Neurologic symptoms
  • Mostly seen in chronic lithium toxicity
  • Sedation
  • Tremor
  • Confusion
  • Ataxia
• Polyuria
• Polydipsia
• Reversible hypothyroidism
• Nephrogenic diabetes insipidus
• Congenital malformations in the heart (teratogenic effect)

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 and may increase the risk of toxicity.

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.