L50. Pharmacology - Pharmacology of Anti-Depressants

• Most drugs treating depression and anxiety target monoamine systems, specifically serotonin and norepinephrine.

Neurobiology of Norepinephrine and Serotonin

• The Raphe nuclei, located in the brainstem, contain all serotoninergic neurons.
• These neurons uniquely express tryptophan hydroxylase (TPH2), converting tryptophan to 5-hydroxytryptophan (5-HTP).
• Aromatic amino acid decarboxylase (AAAD) then decarboxylates 5-HTP to form 5-hydroxytryptamine (5-HT, serotonin).
• Serotonin, like dopamine, is synthesized in the cytoplasm and packed into vesicles by VMAT.
• Within serotonergic neurons, serotonin is degraded by monoamine oxidase and aldehyde dehydrogenase, producing 5-hydroxy-3-indolacetic acid (5-HIAA).
• Serotonin is inactivated via diffusion and reuptake into serotonergic neurons by the serotonin transporter (SERT).
• Post-release, serotonin interacts with seven receptor classes, six of which are metabotropic GPCRs linked to different G proteins, and one ligand-gated ion channel.
• Serotonin receptors are present in the CNS and differentially expressed across brain regions and cell types, with neurons often expressing multiple receptor subtypes.
• Serotonin neurons self-express three receptors for serotonin autoregulation, inhibiting neuronal activity (5-HT1A) and serotonin release (5-HT1B/1D).
• The locus coeruleus, a small nucleus in the pons, contains most norepinephrine-releasing neurons in the brain.
• Remaining norepinephrine neurons are in sparse cell groups extending ventrally and posteriorly, projecting to the entire neuroaxis to provide norepinephrine and epinephrine innervation.
• Norepinephrine neurons express tyrosine hydroxylase, converting tyrosine to L-dopa, and aromatic amino acid decarboxylase (AAAD), removing a carboxy group from L-dopa to produce dopamine.
• Dopamine β-hydroxylase (DBH) converts dopamine into norepinephrine.
• Some cells posterior to the locus coeruleus express phenylethanolamine-N-methyltransferase (PNMT), which synthesizes epinephrine from norepinephrine.
• Catecholamines are synthesized in the cytoplasm and packaged into vesicles by the vesicular monoamine transporter (VMAT).
• Norepinephrine/epinephrine is inactivated by diffusion and reuptake into adrenergic neurons by the norepinephrine transporter (NET).
• Norepinephrine modulates postsynaptic neuron function via α1, α2, and β receptors, all metabotropic GPCRs coupled to different G protein signaling cascades.
• These adrenergic receptors are differentially expressed across brain regions and cell types.
• Norepinephrine cells express α2-adrenergic receptors as autoreceptors, suppressing neuron activity and inhibiting neurotransmitter release.

Anxiety and Depression Treatment

• Anxiety and depression are comorbid mental disorders with no specific diagnostic criteria addressed.
• First clinically effective antidepressants were discovered in the 1950s during trials for antituberculosis (iproniazid) or antipsychotic (imipramine) activity.
• MAO inhibitors (MAOIs; iproniazid) and tricyclic antidepressants (TCAs; imipramine) represent the two main classes of first-generation antidepressants.
• MAOIs are mostly irreversible inhibitors of monoamine oxidase (MAO).
• TCAs inhibit serotonin and/or norepinephrine reuptake by binding to the serotonin transporter (SERT) and/or the NE transporter (NET).
• Imipramine is equieffective at SERT and NET, desipramine preferentially targets NET, and clomipramine is highly selective for SERT.
• TCAs are often metabolized into active compounds with specific preferences for SERT or NET.
• TCAs and MAOIs have significant adverse effects limiting their use.
• MAOIs potentiate action of sympathomimetic amines, like dietary tyramine, risking hypertensive crisis; isocarboxazid, phenelzine and selegiline are modern examples but are seldom used.
• TCAs act at muscarinic, α1-adrenergic, and H1 histamine receptors, leading to several adverse effects and limiting their use.
• Clomipramine remains a treatment for obsessive-compulsive disorder (OCD) due to its potency and SERT selectivity.
• Amitriptyline is used in pain management.
• SSRIs were developed starting with fluoxetine in the 1970s, followed by SNRIs a decade later, based on understanding SERT's role in TCAs.
• Escitalopram, fluoxetine, paroxetine, and sertraline are widely used SSRIs.
• Venlafaxine and duloxetine are commonly used SNRIs.
• Atomoxetine is norepinephrine reuptake inhibitor approved for ADHD treatment exhibiting modest adverse effects.
• Most antidepressants take several weeks to elicit a therapeutic response.
• There is little evidence suggesting depression and anxiety reflect defects in serotonin or norepinephrine signaling.
• Chronic treatment with antidepressants may result in adaptive brain changes, ameliorating symptoms.
• Adaptive responses may involve changes in serotonin and norepinephrine signaling in the brain.
• Antidepressant/antianxiety effects may reflect remodeling of central synaptic networks in response to changes in serotonin/norepinephrine tone.
• Ketamine, an NMDA receptor antagonist offers a rapid and sustained antidepressant response.
• Esketamine, the S isomer of ketamine, was approved in 2019 for treatment-resistant depression.
• Mania is usually treated with mood stabilizers (carbamazepine, valproic acid, or lithium) and antipsychotics.
• Antidepressant treatment in patients prone to mania/hypomania can induce a manic state.
• SSRIs and SNRIs are used for treating generalized anxiety disorder, panic disorder, and agoraphobia.
• Chlorimipramine, Fluoxepine, fluvoxamine, paroxetine (drugs blocking SERT) also treat obsessive-compulsive disorder (OCD).
• Buspirone, a selective agonist of 5-HT1A serotonin receptors, treats generalized anxiety disorder.
• Benzodiazepines like alprazolam and clonazepam are rapid-acting anxiolytics useful in anxiety management, but cause sedation, muscle relaxation, tolerance, and dependence.
• Beta-blockers show usefulness in cases of situational anxiety.

Other Drugs

• Trazodone, developed in the 1960s is an antidepressant approved by the FDA for treatment of depression.
• Trazodone is widely used off-label, in treating conditions including anxiety, depression, insomnia, OCD, and pain management, and binds to GPCRs, monoamine receptors, and SERT with its benefits attributed to blockade of 5-HT2 receptors.
• Bupropion and mirtazapine are also prescribed as antidepressants, interacting with multiple monoamine targets.
• Bupropion is used to support smoking cessation.
• Antidepressants treat chronic and neuropathic pain and migraines, even without anxiety or depression, through effects on spinal cord projections; the SNRI, duloxetine, is approved for joint and muscle pain, while the TCA amitriptyline, treats neuropathic pain.

Explore serotonin synthesis, regulation, and receptor diversity in the CNS. Understand enzymatic processes, SERT's role, and autoreceptor function. Investigate drug effects on serotonin levels and connections to anxiety disorders.