What is the role of various receptors, such as serotonin, dopamine, and GABA (Gamma-Aminobutyric Acid), in psychopharmacology and which medications, including Selective Serotonin Reuptake Inhibitors (SSRIs) like fluoxetine (Prozac) and sertraline (Zoloft), Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) like venlafaxine (Effexor) and duloxetine (Cymbalta), and atypical antipsychotics like quetiapine (Seroquel) and aripiprazole (Abilify), affect these receptors in the treatment of depression and anxiety?

Psychopharmacology Receptor Guide

Major Neurotransmitter Systems and Their Clinical Effects

GABA (Gamma-Aminobutyric Acid) Receptors

Primary inhibitory neurotransmitter in the CNS that decreases neuronal excitability 1

Medications affecting GABA receptors:

• Benzodiazepines (lorazepam, midazolam, diazepam) bind to presynaptic GABA receptors, exerting CNS depressant effects 1
• Lorazepam has fast onset, rapid absorption, and no active metabolites 1
• Midazolam has more rapid onset but shorter duration of action 1
• Diazepam has longer half-life and erratic intramuscular absorption 1

Clinical applications: Acute agitation, anxiety disorders, sedation 1

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Serotonin (5-HT) Receptors

Multiple receptor subtypes with distinct functions in mood, anxiety, and behavior

5-HT Reuptake Inhibition

SSRIs (Selective Serotonin Reuptake Inhibitors):

• Mechanism: Block presynaptic reuptake of serotonin, increasing synaptic availability 2
• First-line agents: Sertraline, escitalopram, paroxetine, fluoxetine, fluvoxamine 3
• Efficacy: NNT = 4.70 for anxiety disorders 3
• Sertraline specifics: No significant affinity for adrenergic, cholinergic, GABA, dopaminergic, histaminergic, or benzodiazepine receptors 2
• Sertraline half-life: 26 hours; steady-state achieved after approximately one week 2
• Escitalopram advantage: Least effect on CYP450 isoenzymes, making it safer for combination therapy 4, 5

SNRIs (Serotonin-Norepinephrine Reuptake Inhibitors):

• Mechanism: Inhibit presynaptic reuptake of both serotonin AND norepinephrine 1
• Agents: Venlafaxine, duloxetine, desvenlafaxine, levomilnacipran 1
• Efficacy: NNT = 4.94 for anxiety disorders (similar to SSRIs) 3
• Venlafaxine specifics: Potent inhibitor of serotonin and norepinephrine reuptake, weak dopamine reuptake inhibitor 6
• Venlafaxine half-life: 5 hours (parent drug), 11 hours (active metabolite ODV) 6
• Clinical advantage: May be more effective than SSRIs in treatment-resistant depression due to dual mechanism 1, 7

Specific 5-HT Receptor Subtypes

5-HT1A receptors:

• Aripiprazole acts as partial agonist at 5-HT1A receptors (Ki = 1.7 nM) 8
• Modulates stress responses and anxiety 9

5-HT2A receptors:

• Aripiprazole acts as antagonist at 5-HT2A receptors (Ki = 3.4 nM) 8
• Atypical antipsychotics (second-generation) are serotonin-dopamine receptor antagonists 1
• Antagonism reduces agitation and psychotic symptoms 1

5-HT2C receptors:

• Aripiprazole has moderate affinity as partial agonist (Ki = 15 nM) 8
• Involved in mood regulation and appetite 9

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Dopamine Receptors

Primary targets for antipsychotic medications; involved in motivation, reward, and psychosis

D2 Receptors (Postsynaptic)

Typical antipsychotics:

• High-potency agents (haloperidol, droperidol): Strong D2 antagonism, less sedating, MORE extrapyramidal symptoms 1
• Low-potency agents (chlorpromazine, thioridazine): Weaker D2 antagonism, MORE sedating, FEWER extrapyramidal symptoms 1

Atypical antipsychotics:

• Mechanism: Serotonin-dopamine receptor antagonists with varying D2 affinity 1
• Quetiapine: Used off-label for anxiety and depression; combined serotonin-dopamine antagonism 1
• Aripiprazole (unique): Partial D2 agonist (Ki = 0.34 nM), not pure antagonist 1, 8
  • Considered "third-generation" antipsychotic due to partial agonist activity 1
  • Also partial agonist at D3 receptors (Ki = 0.8 nM) 8
  • Steady-state achieved within 14 days; half-life 75 hours (parent), 94 hours (metabolite) 8

Clinical applications: Augmentation in treatment-resistant depression and anxiety 10, 9, 11

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Norepinephrine (Noradrenergic) Receptors

Modulate stress responses including alertness, arousal, attentiveness, and vigilance 1

Medications affecting norepinephrine:

• SNRIs (venlafaxine, duloxetine): Inhibit norepinephrine reuptake alongside serotonin 1, 6
• Mechanism paradox: Despite association with "fight or flight" response, noradrenergic medications effectively treat anxiety through complex neurotransmitter interactions 1
• Duloxetine: Only SNRI FDA-approved for generalized anxiety disorder in children/adolescents age 7+ 1

α-adrenergic receptors:

• Clonidine: Presynaptic α-agonist used off-label for ADHD and opiate withdrawal; causes somnolence 1
• Aripiprazole: Moderate affinity for α1-adrenergic receptors (Ki = 57 nM) 8

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Histamine Receptors

Antagonism associated with sedation and weight gain

Medications with histamine effects:

• Diphenhydramine and hydroxyzine: H1 antagonists with sedative effects, used for insomnia and acute agitation 1
• Aripiprazole: Moderate affinity for H1 receptors (Ki = 61 nM), lower sedation risk than other atypicals 8
• Low-potency typical antipsychotics: Greater histamine blockade contributes to sedation 1

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Cholinergic (Muscarinic) Receptors

Antagonism causes anticholinergic side effects: dry mouth, constipation, urinary retention, confusion

Medications with cholinergic effects:

• Sertraline: No significant affinity for cholinergic muscarinic receptors 2
• Venlafaxine: No significant affinity for muscarinic receptors 6
• Aripiprazole: No appreciable affinity for muscarinic receptors (IC50 >1000 nM) 8
• Low-potency typical antipsychotics: Greater anticholinergic effects than high-potency agents 1

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Clinical Decision Algorithm for Anxiety and Depression

First-Line Treatment Selection

Start with SSRIs (sertraline, escitalopram) or SNRIs (duloxetine for age 7+, venlafaxine) 3

• SSRIs and SNRIs have similar efficacy (NNT ~4.7-4.9) and dropout rates comparable to placebo 3
• Escitalopram preferred when drug interactions are a concern due to minimal CYP450 effects 4, 5

Treatment-Resistant Cases (After 8-12 Weeks at Therapeutic Dose)

Option 1: Switch to different class

• SSRI → SNRI (venlafaxine, duloxetine) shows superior response in treatment-resistant cases 1, 7

Option 2: Augmentation with atypical antipsychotic

• Aripiprazole: Partial D2 agonist, 5-HT1A partial agonist, 5-HT2A antagonist 8, 9
• Quetiapine: Serotonin-dopamine antagonist for refractory cases 1, 10
• Remission rates 61-76% when combining atypicals with SSRIs 11

Option 3: Add cognitive-behavioral therapy

• Combination therapy superior to medication alone 3, 4

Acute Agitation Management

Combination of benzodiazepine + antipsychotic is expert-recommended regimen 1

• Benzodiazepine targets GABA receptors for rapid anxiolysis 1
• Antipsychotic targets dopamine/serotonin receptors for behavioral control 1

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Critical Safety Considerations

Serotonin Syndrome Risk

Avoid combining multiple serotonergic agents (SSRIs + SNRIs + MAOIs) 4, 5

• Symptoms: Mental status changes, neuromuscular hyperactivity, autonomic hyperactivity 5

Discontinuation Syndrome

Taper all antidepressants gradually 4

• Escitalopram has lower discontinuation risk than paroxetine or sertraline 5
• Venlafaxine associated with significant discontinuation symptoms 1

QTc Prolongation

Maximum escitalopram dose: 20 mg daily 5

• Higher doses increase cardiac risk without additional benefit 5

Suicidality Monitoring

Highest risk during first 1-2 months of treatment or after dose changes 1, 5

• Monitor closely in adolescents and young adults up to age 24 1