CNS Pharmacology: Antidepressants and Lithium

Introduction/Overview

Central nervous system (CNS) pharmacology encompasses a broad array of agents that modulate neurotransmission, neuronal excitability, and neurochemical pathways implicated in mood regulation. Among these, antidepressants and lithium represent cornerstone therapies for major depressive disorder and bipolar affective disorders, respectively. Their widespread clinical application, complex pharmacodynamics, and significant safety profiles underscore the necessity for comprehensive understanding by future clinicians and pharmacists.

Clinical relevance is evident: depression remains one of the leading causes of disability worldwide, while bipolar disorder imposes substantial morbidity and mortality. Antidepressants and lithium not only ameliorate mood symptoms but also confer neuroprotective and cognitive benefits that may influence long-term disease trajectories. Consequently, mastery of their pharmacological attributes is essential for optimizing patient outcomes, anticipating adverse events, and navigating therapeutic challenges.

• Recognize the major classes of antidepressants and their distinct mechanisms of action.
• Explain the pharmacokinetic properties of representative agents within each class.
• Identify therapeutic indications, off‑label uses, and monitoring requirements for antidepressants and lithium.
• Characterize common and serious adverse effects, and describe strategies for risk mitigation.
• Appreciate drug‑drug interactions, contraindications, and special population considerations.

Classification

Antidepressants

• Selective Serotonin Reuptake Inhibitors (SSRIs) – e.g., fluoxetine, sertraline, citalopram, escitalopram, paroxetine.
• Serotonin–Norepinephrine Reuptake Inhibitors (SNRIs) – e.g., venlafaxine, duloxetine, desvenlafaxine.
• Tricyclic Antidepressants (TCAs) – e.g., amitriptyline, imipramine, nortriptyline.
• Monaamine Oxidase Inhibitors (MAOIs) – e.g., phenelzine, selegiline, isocarboxazid.
• Atypical Antidepressants – e.g., bupropion, mirtazapine, trazodone, vortioxetine.

Lithium

Lithium carbonate is the only licensed monotherapy for maintenance treatment of bipolar disorder. It is also employed as an adjunct in treatment‑resistant depression and as a mood stabilizer in schizoaffective disorder.

Mechanism of Action

Selective Serotonin Reuptake Inhibitors (SSRIs)

SSRIs competitively inhibit the presynaptic serotonin transporter (SERT), thereby elevating extracellular serotonin concentrations. The resulting modulation of postsynaptic 5‑HT receptors is believed to underlie the therapeutic effect. Evidence suggests that chronic SSRI exposure produces downstream neuroplastic changes, including increased brain‑derived neurotrophic factor (BDNF) expression and enhanced hippocampal neurogenesis, although the precise causal pathways remain incompletely defined.

Serotonin–Norepinephrine Reuptake Inhibitors (SNRIs)

SNRIs block the reuptake of both serotonin and norepinephrine by antagonizing SERT and the norepinephrine transporter (NET). The dual neurotransmitter elevation is postulated to provide greater efficacy in patients with comorbid anxiety or pain syndromes. Similar neuroplastic adaptations seen with SSRIs may also occur with SNRIs, though differential receptor engagement could modulate the magnitude of these effects.

Tricyclic Antidepressants (TCAs)

TCAs inhibit reuptake of serotonin and norepinephrine via blockade of SERT and NET, but possess additional pharmacological activities. They antagonize postsynaptic histamine H1, alpha‑1 adrenergic, and muscarinic acetylcholine receptors, which account for many of their anticholinergic and sedative side effects. The inhibition of norepinephrine reuptake is typically more pronounced than that of serotonin, a feature that may contribute to their efficacy in atypical depression and chronic pain conditions.

Monaamine Oxidase Inhibitors (MAOIs)

MAOIs irreversibly inhibit the enzyme monoamine oxidase (MAO), which catabolizes monoamines such as serotonin, norepinephrine, dopamine, and tyramine. By preventing the oxidative deamination of these neurotransmitters, MAOIs increase their synaptic availability. The dietary restrictions required to avoid tyramine‑induced hypertensive crises stem from the systemic inhibition of MAO‑A, which metabolizes dietary tyramine.

Atypical Antidepressants

Atypical agents exhibit diverse mechanisms:

• Bupropion functions primarily as a norepinephrine–dopamine reuptake inhibitor (NDRI), with negligible serotonergic activity.
• Mirtazapine antagonizes presynaptic alpha‑2 adrenergic autoreceptors, enhancing norepinephrine and serotonin release, and blocks postsynaptic 5‑HT2 and 5‑HT3 receptors.
• Trazodone acts as a serotonin antagonist and reuptake inhibitor (SARI) with prominent 5‑HT2A antagonism, contributing to its sedative properties.
• Vortioxetine combines serotonin transporter inhibition with modulatory effects on various 5‑HT receptor subtypes.

Lithium

Lithium’s precise mechanism remains incompletely elucidated, yet several converging pathways are implicated. It inhibits inositol monophosphatase, thereby disrupting the phosphatidylinositol signaling cascade; it also impairs glycogen synthase kinase‑3β (GSK‑3β) activity, influencing gene transcription and neuronal resilience. Inhibition of phospholipase C and downstream calcium mobilization is another proposed mechanism. These actions collectively contribute to mood stabilization and neuroprotection, including promotion of neurogenesis and reduction of excitotoxicity.

Pharmacokinetics

SSRIs

Orally administered SSRIs achieve peak plasma concentrations within 1–4 hours. Bioavailability varies: fluoxetine (~70 %), sertraline (~80 %), citalopram (~60 %). Metabolism occurs primarily via hepatic cytochrome P450 enzymes—fluoxetine via CYP2D6, sertraline via CYP2B6/CYP2C19, and citalopram via CYP2C19/CYP2D6. Elimination half‑lives range from 2–4 days (fluoxetine’s active metabolite norfluoxetine extends the duration). Renal excretion accounts for 20–30 % of the dose; hepatic impairment necessitates dose adjustment in severe cases.

SNRIs

Venlafaxine is rapidly absorbed (Tmax ≈ 2 h), metabolized by CYP2D6 to O-desmethylvenlafaxine, and has a half‑life of 5–7 h. Duloxetine exhibits a half‑life of 12 h, with metabolism via CYP1A2 and CYP2D6. Desvenlafaxine, the active metabolite of venlafaxine, is excreted unchanged in urine, and its half‑life extends to 12–13 h in patients with renal impairment.

TCAs

TCAs display high oral bioavailability (>80 %) and rapid absorption (Tmax ≈ 2–4 h). Metabolism involves extensive hepatic CYP2D6, CYP3A4, and CYP1A2 pathways. Pharmacokinetic variability is pronounced due to polymorphic enzyme activity. Elimination half‑lives vary widely: amitriptyline (12–36 h), imipramine (7–12 h). Renal excretion of metabolites accounts for 30–50 % of the dose; hepatic impairment may prolong half‑life.

MAOIs

Phenelzine is rapidly absorbed (Tmax ≈ 3 h), with a short plasma half‑life of 1–2 h, but its pharmacodynamic effect persists due to irreversible MAO inhibition. Metabolism occurs via hepatic glucuronidation. Selegiline, administered orally, is partially metabolized to amphetamine derivatives, contributing to its sympathomimetic side effects. Renal excretion of metabolites is significant; dose adjustment is advised in renal dysfunction.

Atypical Antidepressants

Bupropion’s Tmax is ~3 h, with a half‑life of 21 h; it undergoes hepatic metabolism via CYP2B6 to hydroxybupropion and threohydrobupropion. Mirtazapine has a half‑life of 20–40 h, metabolized primarily by CYP3A4. Trazodone’s half‑life is ~7 h, with hepatic metabolism via CYP3A4. Vortioxetine exhibits a half‑life of 66 h, extensively metabolized by CYP3A4 and CYP2D6. Renal excretion is minimal for most of these agents.

Lithium

Lithium carbonate is nearly 100 % absorbed from the gastrointestinal tract. Peak serum concentrations are attained within 1–2 hours after an oral dose. Distribution is extensive but does not cross the blood–brain barrier efficiently; central nervous system concentrations approximate plasma levels. Renal excretion is responsible for the majority of lithium elimination, occurring via glomerular filtration and tubular reabsorption. The elimination half‑life ranges from 18 h in healthy adults to 30–40 h in elderly or those with reduced renal function. Due to its narrow therapeutic index, therapeutic drug monitoring (TDM) is essential.

Therapeutic Uses/Clinical Applications

Antidepressants

All antidepressant classes are approved for major depressive disorder (MDD). SSRIs and SNRIs also receive approval for generalized anxiety disorder (GAD), panic disorder, and obsessive–compulsive disorder (OCD). TCAs are indicated for MDD, atypical depression, and neuropathic pain, though their use is limited by safety concerns. MAOIs are reserved for treatment‑resistant depression, atypical depression, and melancholic depression; they are also employed in OCD. Atypical agents serve specific indications: bupropion for depression and smoking cessation; mirtazapine for depressive disorders with insomnia; trazodone for depression with insomnia; vortioxetine for depressive disorders with cognitive deficits.

Off‑Label Uses

Antidepressants are frequently prescribed for chronic pain syndromes (e.g., diabetic neuropathy, fibromyalgia), migraine prophylaxis, and certain dermatologic conditions (e.g., pruritus). SSRIs and SNRIs are also used for hot flashes in post‑menopausal women. Lithium is employed for augmentation in treatment‑resistant depression, for catatonia, and as a prophylactic agent in unipolar depression with high relapse risk. Off‑label use of lithium in certain neuropsychiatric conditions (e.g., schizoaffective disorder) is common, though evidence remains mixed.

Lithium

Lithium is first‑line for acute mania and rapid cycling bipolar disorder. It is also indicated for maintenance therapy in bipolar I disorder, with evidence supporting reduction in suicide risk. Lithium’s anti‑suicidal effect has led to its use in high‑risk patients with major depressive disorder, although this remains controversial. Other indications include adjunctive therapy in schizoaffective disorder and catatonic episodes.

Adverse Effects

Antidepressants

SSRIs frequently produce nausea, diarrhea, sexual dysfunction, insomnia, and increased risk of bleeding when combined with non‑steroidal anti‑inflammatory drugs (NSAIDs) or anticoagulants. Rarely, serotonin syndrome may occur, particularly when combined with serotonergic agents or MAOIs.

SNRIs can cause hypertension, tachycardia, and increased serum prolactin. They share many SSRI side effects but may also precipitate orthostatic hypotension.

TCAs are associated with anticholinergic effects (dry mouth, blurred vision, urinary retention), sedation, weight gain, and cardiac conduction disturbances, including QT prolongation and arrhythmias. In overdose, severe cardiotoxicity and central nervous system depression are life‑threatening.

MAOIs pose risks of hypertensive crisis with tyramine‑rich foods, orthostatic hypotension, and serotonin syndrome when combined with serotonergic drugs. Seizure risk is increased in patients with seizure disorders.

Atypical Antidepressants present class‑specific profiles: bupropion can induce agitation, insomnia, and seizures at high doses; mirtazapine is associated with weight gain, sedation, and orthostatic hypotension; trazodone may cause priapism and QT prolongation; vortioxetine may result in nausea and headache.

Lithium

Common adverse effects include tremor, polyuria, polydipsia, weight gain, and mild cognitive dulling. In severe cases, lithium toxicity manifests as ataxia, dysarthria, seizures, renal impairment, and cardiac conduction abnormalities. A black‑box warning is issued for lithium due to its narrow therapeutic index and potential for serious toxicity, particularly in the setting of renal dysfunction, dehydration, or drug interactions that alter renal clearance.

Drug Interactions

Antidepressants

• SSRIs/SNRIs inhibit CYP2D6 and/or CYP2C19, raising serum levels of drugs metabolized by these enzymes (e.g., propranolol, codeine). They also increase serotonin levels when combined with serotonergic agents (e.g., tramadol, MDMA), raising serotonin‑syndrome risk.
• TCAs compete for CYP2D6 and CYP3A4; co‑administration with CYP inhibitors (e.g., fluvoxamine) can markedly elevate TCA levels. Anticholinergic burden is additive when combined with other anticholinergic agents.
• MAOIs interact with tyramine‑rich foods (cheese, cured meats) and can precipitate hypertensive crises. Concomitant use with SSRIs or SNRIs increases serotonin‑syndrome risk.
• Atypical Antidepressants bupropion is a potent CYP2B6 inhibitor; co‑administration with drugs metabolized by CYP2B6 can lead to increased plasma concentrations. Mirtazapine is metabolized by CYP3A4; inhibitors (e.g., ketoconazole) may increase mirtazapine levels.

Lithium

• Diuretics (furosemide, thiazides) decrease renal lithium clearance, precipitating toxicity.
• Non‑steroidal anti‑inflammatory drugs (NSAIDs) reduce glomerular filtration rate, elevating lithium levels.
• ACE inhibitors and ARBs can also reduce lithium elimination.
• Beta‑blockers may mask lithium‑induced tremor, delaying recognition of toxicity.
• Serotonergic agents may potentiate lithium’s neurotoxic effects.

Special Considerations

Pregnancy and Lactation

SSRIs are generally considered acceptable during pregnancy, though selective reports of congenital heart defects and persistent pulmonary hypertension of the newborn exist. MAOIs are contraindicated due to maternal toxicity and fetal risk. TCAs carry a risk of neonatal cardiac conduction abnormalities. Lithium is associated with a 0.3–0.5 % risk of Ebstein anomaly; however, the absolute risk remains low. Lithium therapy may be continued in lactation with caution, as it is excreted in breast milk; infants should be monitored for signs of toxicity.

Pediatric and Geriatric Populations

In children and adolescents, SSRIs and SNRIs may increase the risk of suicidal ideation; careful monitoring is required. TCAs are seldom used in pediatrics due to safety concerns. Lithium is used cautiously in older adults because of reduced renal clearance and increased sensitivity to dehydration. Polypharmacy is common in geriatrics; drug interactions and anticholinergic load warrant meticulous review.

Renal and Hepatic Impairment

SSRIs and SNRIs are metabolized hepatically; dose adjustments may be necessary in severe hepatic dysfunction. TCAs exhibit significant hepatic metabolism; caution is advised. MAOIs require careful dose titration in hepatic impairment. Lithium clearance is markedly reduced in renal insufficiency; serum lithium monitoring and dose reduction are mandatory. For patients with hepatic or renal disease, therapeutic drug monitoring (TDM) should be performed routinely.

Summary/Key Points

• Antidepressants encompass multiple pharmacological classes, each with distinct mechanisms, pharmacokinetics, and side‑effect profiles.
• SSRIs and SNRIs act by inhibiting serotonin and/or norepinephrine reuptake; TCAs block reuptake and exert additional receptor antagonism.
• MAOIs irreversibly inhibit monoamine oxidase, necessitating dietary restrictions; atypical agents target diverse neurotransmitter systems.
• Lithium stabilizes mood via inhibition of inositol monophosphatase and GSK‑3β, with a narrow therapeutic index requiring regular serum monitoring.
• Adverse effect profiles vary: SSRIs commonly cause sexual dysfunction; TCAs carry anticholinergic and cardiotoxic risks; MAOIs risk hypertensive crises; lithium toxicity manifests with tremor, ataxia, and renal impairment.
• Drug interactions are frequent; CYP450 inhibition, serotonergic synergy, and renal clearance alterations must be considered.
• Special populations—pregnancy, lactation, pediatrics, geriatrics, renal/hepatic impairment—require individualized dosing and monitoring strategies.
• Clinical decision‑making should balance efficacy, safety, patient preference, and comorbid conditions to optimize therapeutic outcomes.

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