Pharmacology: Antidepressants and Mood Disorders

Antidepressants: Treatment of Depression and Mania

• Symptoms of depression: intense feelings of sadness, hopelessness, despair, and inability to experience pleasure in usual activities, changes in sleep patterns and appetite, loss of energy, and suicidal thoughts.
• Mania is characterized by the opposite behavior: enthusiasm, rapid thought and speech patterns.

Types of Antidepressants

• Selective Serotonin Reuptake Inhibitors (SSRIs)
  • Examples: Citalopram, Escitalopram, Fluoxetine, Fluvoxamine, Paroxetine, Sertraline
• Serotonin/Norepinephrine Reuptake Inhibitors (SNRIs)
  • Examples: Desvenlafaxine, Duloxetine, Venlafaxine
• Atypical Antidepressants
  • Examples: Bupropion, Mirtazapine, Nefazodone, Trazodone
• Tricyclic Antidepressants (TCAs)
  • Examples: Amitriptyline, Amoxapine, Clomipramine, Desipramine, Doxepin, Imipramine, Maprotiline, Nortriptyline, Protriptyline, Trimipramine
• Monoamine Oxidase Inhibitors (MAOIs)
  • Examples: Isocarboxazid, Phenelzine, Selegiline, Tranylcypromine

Mechanism of Antidepressant Drugs

• Most clinically useful antidepressant drugs potentiate the actions of norepinephrine and/or serotonin in the brain.
• The biogenic amine theory proposes that depression is due to a deficiency of monoamines, such as norepinephrine and serotonin, at certain key sites in the brain.
• Mania is caused by an overproduction of these neurotransmitters.

Adverse Effects

• Headache, sweating, anxiety, and agitation
• Gastrointestinal effects (nausea, vomiting, diarrhea)
• Weakness and fatigue
• Sexual dysfunction
• Changes in weight
• Sleep disturbances (insomnia and somnolence)
• Potential for drug-drug interactions

Sexual Dysfunction

• Loss of libido, delayed ejaculation, and anorgasmia
• One option for managing SSRI-induced sexual dysfunction is to replace with an antidepressant having fewer sexual side effects, e.g., bupropion or mirtazapine.

Discontinuation Syndrome

• After abrupt withdrawal, agents with shorter half-lives and having inactive metabolites have a higher risk for adverse reaction.
• Fluoxetine has the lowest risk of causing an SSRI discontinuation syndrome.
• Signs of discontinuation syndrome include headache, malaise, and flu-like symptoms, agitation, and irritability.

Serotonin/Norepinephrine Reuptake Inhibitors (SNRIs)

• Inhibit the reuptake of both serotonin and norepinephrine.
• May be effective in treating depression in patients in whom SSRIs are ineffective.
• Depression is often accompanied by chronic painful symptoms, such as backache, muscle aches, postherpetic neuralgia, and fibromyalgia, against which SSRIs are also relatively ineffective.

Atypical Antidepressants

• The atypical antidepressants have actions at several different sites.
• They are not more efficacious than the TCAs or SSRIs, but their side effect profiles are different.

Bupropion

• Acts as a weak dopamine and norepinephrine reuptake inhibitor to alleviate the symptoms of depression.
• Its short half-life may require more than once-a-day dosing or the administration of an extended-release formulation.
• Also assists in decreasing the craving and attenuating the withdrawal symptoms for nicotine in tobacco users trying to quit smoking.

Mirtazapine

• Enhances serotonin and norepinephrine neurotransmission via mechanisms related to its ability to block presynaptic α2 receptors and block 5-HT2 receptors.
• It is a sedative because of its potent antihistaminic activity.
• Causes increased appetite and weight gain.
• It is markedly sedating, which may be an advantage in depressed patients having difficulty sleeping.

Tricyclic Antidepressants (TCAs)

• Block norepinephrine and serotonin reuptake into the neuron.
• Differ in adverse effects relative to the newer class of antidepressants.
• Include the tertiary amines, such as imipramine, amitriptyline, clomipramine, doxepin, and trimipramine.
• Include the secondary amines, such as desipramine and nortriptyline.
• Include the tetracyclics, such as protriptyline, maprotiline, and amoxapine.

Mechanism of Action of TCAs

• Inhibit the reuptake of norepinephrine and serotonin into the neuron.
• Block serotonergic, α-adrenergic, histaminic, and muscarinic receptors leading to adverse effects.

Monoamine Oxidase Inhibitors (MAOIs)

• May irreversibly or reversibly inactivate the enzyme, permitting neurotransmitter molecules to escape degradation and accumulate within the presynaptic neuron and leak into the synaptic space.
• Cause activation of norepinephrine and serotonin receptors, and may be responsible for their indirect antidepressant action.

Mechanism of Action of MAOIs

• Inhibit both MAO in the brain and MAO in the liver and gut that catalyze oxidative deamination of drugs and potentially toxic substances.
• Show a high incidence of drug-drug and drug-food interactions.
• Selegiline administered as the transdermal patch may produce less inhibition of gut and hepatic MAO at low doses because it avoids first-pass metabolism.