Neurobiology and Pharmacology of Mood Regulation

This delay is thought to be explained by the desensitization of presynaptic autoreceptors. Initially, increased neurotransmitter levels trigger "autoinhibitory feedback," which actually limits further release. With chronic treatment, these autoreceptors become desensitized, reducing the inhibition and allowing for sustained, enhanced postsynaptic receptor activity.

Exam Tip: If asked about the mechanism behind the delayed onset of antidepressants, look for "desensitization of presynaptic autoreceptors".

Pharmacological Classes of Antidepressants

Antidepressants are categorized by their primary mechanism of action: inhibiting reuptake, inhibiting degradation, or modulating other pathways.

1. Reuptake Inhibitors

These drugs prevent the "recycling" of neurotransmitters, leaving more available in the synapse.

• Selective Serotonin Reuptake Inhibitors (SSRIs): These specifically target the serotonin transporter (SERT). Examples include Fluoxetine (Prozac) and Sertraline. While highly selective, at high doses, they may also bind to NE transporters.
• Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs): These block the reuptake of both 5-HT and NE in a concentration-dependent manner. Examples include Venlafaxine and Duloxetine.
• Norepinephrine Reuptake Inhibitors (NRIs): These selectively block NE uptake, such as Atomoxetine, and are often used in treating ADHD.
• Tricyclic Antidepressants (TCAs): An older class that inhibits the reuptake of both 5-HT and NE. TCAs with secondary amines primarily affect the NE system, while those with tertiary amines primarily affect the 5-HT system.

Clinical Warning: TCAs have a narrow therapeutic index. Overdosing can lead to lethal cardiac arrhythmias, seizures, and death.

2. Degradation and Storage Inhibitors

• Monoamine Oxidase Inhibitors (MAOIs): These block the enzyme (MAO) responsible for breaking down monoamines. By inhibiting the functional flavin moiety of MAO, they increase the amount of 5-HT and NE available in the presynaptic cytoplasm for storage and subsequent release.
  • Note: MAOIs require strict dietary restrictions, specifically avoiding foods high in tyramine, to prevent dangerous interactions.
• Storage Inhibitors: These drugs (like Reserpine) displace neurotransmitters from their storage vesicles, which can actually induce depression.

3. Other Agents and Mood Stabilizers

• Lithium: A primary treatment for mania and bipolar disorder. It enters cells via sodium channels and inhibits inositol phosphatase, which alters signaling cascades.
• Anticonvulsants: Drugs like Carbamazepine (which blocks voltage-gated sodium channels) and Valproic Acid (which inhibits T-type calcium channels) are used as mood stabilizers in bipolar disorder.
• Bupropion: Useful for treating bipolar disorder and reducing nicotine withdrawal.

Clinical Applications: Matching Drug to Diagnosis

Not all depression is the same. Treatment efficacy often depends on the specific subtype of the disorder:

FDA Warning: All antidepressant drugs increase the risk of suicidal ideation, particularly in younger patients.

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Summary Table of Common Adverse Effects