5.2 Antidepressants and mood stabilizers

Antidepressants and Mood Stabilizers

Antidepressants and mood stabilizers target neurotransmitter systems in the brain to treat conditions like major depressive disorder and bipolar disorder. Understanding their mechanisms, therapeutic uses, and adverse effect profiles is essential for selecting the right drug for the right patient.

This section covers the major antidepressant classes (MAOIs, TCAs, SSRIs, SNRIs, and atypicals), mood stabilizers (lithium and anticonvulsants), their clinical applications, and the side effects and interactions you need to know.

Antidepressant Mechanisms of Action

Classification of Antidepressants

Antidepressants are grouped into classes based on how they alter neurotransmitter activity. The core idea across most classes is the same: increase the availability of monoamine neurotransmitters (serotonin, norepinephrine, and/or dopamine) in the synaptic cleft. The classes differ in which neurotransmitters they target and how they increase availability.

• MAOIs inhibit monoamine oxidase, the enzyme that breaks down serotonin, norepinephrine, and dopamine. By blocking this enzyme, all three neurotransmitters accumulate.
• TCAs block the reuptake transporters for serotonin and norepinephrine, but with poor selectivity. They also bind histamine and acetylcholine receptors, which accounts for many of their side effects.
• SSRIs selectively block the serotonin transporter (SERT), increasing serotonin in the synaptic cleft without significantly affecting other neurotransmitter systems.
• SNRIs block reuptake of both serotonin and norepinephrine, giving a dual-action profile.
• Atypical antidepressants don't fit neatly into the other categories. Their mechanisms vary and include receptor antagonism, modulation of neurotransmitter release, and dopamine/norepinephrine reuptake inhibition.

Detailed Mechanisms of Action

MAOIs prevent the enzymatic breakdown of monoamines, raising overall brain levels of serotonin, norepinephrine, and dopamine. Examples: phenelzine, tranylcypromine. These are rarely first-line today because of their dietary restrictions and interaction risks (more on that below).

TCAs block serotonin and norepinephrine reuptake transporters, but they also antagonize histaminic ($H_1$) and muscarinic acetylcholine receptors. This broad receptor profile makes them effective but causes more side effects. Examples: amitriptyline, nortriptyline. Nortriptyline is relatively more selective for norepinephrine reuptake, while amitriptyline has stronger serotonin and antihistamine effects.

SSRIs target SERT with high selectivity. By blocking serotonin reuptake, they increase serotonin concentration in the synapse. Their selectivity is why they have a more favorable side effect profile than TCAs. Examples: fluoxetine, sertraline, escitalopram.

SNRIs inhibit both the serotonin transporter and the norepinephrine transporter (NET). This dual mechanism can be advantageous for patients with both mood and pain symptoms. Examples: venlafaxine, duloxetine. At lower doses, venlafaxine acts more like an SSRI; norepinephrine reuptake inhibition becomes more prominent at higher doses.

Atypical antidepressants each have distinct mechanisms:

• Bupropion inhibits dopamine and norepinephrine reuptake (no serotonin activity, which is why it has a lower risk of sexual side effects)
• Mirtazapine antagonizes $\alpha_2$-adrenergic autoreceptors (increasing norepinephrine and serotonin release) and blocks $5\text{-}HT_2$ and $5\text{-}HT_3$ serotonin receptors, plus $H_1$ histamine receptors (causing sedation and weight gain)
• Vortioxetine combines SERT inhibition with agonism and antagonism at multiple serotonin receptor subtypes

Pharmacological Effects of SSRIs, SNRIs, and TCAs

SSRI Effects and Characteristics

SSRIs enhance serotonergic neurotransmission by selectively blocking SERT. The clinical result is mood elevation, reduced anxiety, improved sleep regulation, and appetite stabilization.

A critical point for exams: SSRIs have a delayed onset of action, typically 2 to 4 weeks before full therapeutic benefit appears. This lag is thought to involve downstream receptor adaptations (like desensitization of somatodendritic $5\text{-}HT_{1A}$ autoreceptors), not just the immediate increase in synaptic serotonin.

SSRIs are generally well-tolerated compared to TCAs and MAOIs, which is a major reason they're first-line for depression and many anxiety disorders. Common examples: fluoxetine, sertraline, escitalopram.

SNRI Mechanisms and Impacts

SNRIs block reuptake of both serotonin and norepinephrine, producing improvements in mood, energy, and motivation. The norepinephrine component also contributes to their usefulness in chronic pain conditions like fibromyalgia and diabetic neuropathic pain. Duloxetine, for instance, has FDA approval for both depression and several pain indications.

SNRIs are effective for depression and anxiety disorders. In some patients, the dual mechanism may produce a response when SSRIs alone haven't worked. Common examples: venlafaxine, duloxetine, desvenlafaxine.

TCA Pharmacology and Effects

TCAs block serotonin and norepinephrine reuptake, similar to SNRIs, but they also interact with histamine, acetylcholine, and $\alpha_1$-adrenergic receptors. This broad receptor binding is a double-edged sword: it makes TCAs potent for severe depression and certain pain conditions, but it also produces a wider range of side effects.

TCAs have a lower therapeutic index than SSRIs or SNRIs, meaning the margin between a therapeutic dose and a toxic dose is smaller. Overdose can be fatal (cardiac arrhythmias are the primary concern), so dosing and monitoring require extra care. This is a key reason TCAs are generally reserved for treatment-resistant cases rather than used first-line. Common examples: amitriptyline, nortriptyline, imipramine.

Mood Stabilizers for Bipolar Disorder

Lithium as a Mood Stabilizer

Lithium remains the gold-standard mood stabilizer, especially for classic bipolar I disorder with distinct manic and depressive episodes. Its mechanism isn't fully understood, but it modulates multiple intracellular signaling pathways, including inhibition of inositol monophosphatase and glycogen synthase kinase-3 (GSK-3), producing neuroprotective and mood-stabilizing effects.

Key clinical facts about lithium:

• Prevents or reduces the severity of both manic and depressive episodes
• Reduces suicide risk in bipolar patients, a unique and clinically significant benefit
• Has a narrow therapeutic index (therapeutic range roughly 0.6–1.2 mEq/L), so serum levels must be monitored regularly
• Toxicity presents as tremor, GI disturbance, cognitive impairment, and at higher levels, renal dysfunction, seizures, and cardiac arrhythmias
• Long-term use can cause hypothyroidism and nephrogenic diabetes insipidus, requiring periodic thyroid and renal function tests

Anticonvulsants as Mood Stabilizers

Several anticonvulsants are used as mood stabilizers. They work by modulating neuronal excitability and neurotransmitter release, dampening the extreme mood swings of bipolar disorder.

• Valproic acid (valproate) is effective for acute manic episodes and mixed states. It enhances GABA activity and blocks voltage-gated sodium channels. Side effects include weight gain, tremor, GI upset, and hepatotoxicity (liver function tests should be monitored). It's also teratogenic, so it's contraindicated in pregnancy when possible.
• Carbamazepine is particularly useful for rapid-cycling bipolar disorder. It primarily blocks voltage-gated sodium channels. Side effects include sedation, dizziness, and rare but serious aplastic anemia and Stevens-Johnson syndrome. It's also a potent CYP450 inducer, creating many drug interactions.
• Lamotrigine stands out for its effectiveness in bipolar depression specifically, rather than mania. It modulates glutamate release by blocking sodium channels. The major safety concern is a risk of Stevens-Johnson syndrome, which is minimized by slow dose titration over several weeks.

Therapeutic Considerations for Mood Stabilizers

Mood stabilizers are frequently combined with antipsychotics or antidepressants for comprehensive bipolar management. Therapeutic effects typically develop over several weeks, and long-term, consistent use is necessary for optimal outcomes.

Regular monitoring is essential: serum drug levels (especially for lithium and valproate), hepatic function, renal function, thyroid function (for lithium), and complete blood counts (for carbamazepine). Dosage adjustments are guided by clinical response, tolerability, and lab values.

Patient education matters here more than with many drug classes. Patients need to understand why adherence is critical even when they feel well, why they can't abruptly stop medication, and what early signs of toxicity look like.

Therapeutic Uses of Antidepressants and Mood Stabilizers

Applications of Antidepressants

The primary indication for antidepressants is major depressive disorder (MDD), but their uses extend well beyond that:

• Anxiety disorders: SSRIs and SNRIs are first-line for generalized anxiety disorder (GAD), panic disorder, and social anxiety disorder
• OCD: SSRIs (often at higher doses than used for depression) are first-line; clomipramine, a TCA, is also effective
• Chronic pain: SNRIs (especially duloxetine) and TCAs (especially amitriptyline) are used for neuropathic pain and fibromyalgia
• PTSD: Sertraline and paroxetine (both SSRIs) have FDA approval for PTSD

SSRIs and SNRIs are first-line for most of these conditions due to their favorable side effect profiles. TCAs are reserved for treatment-resistant depression or specific pain syndromes. Atypical antidepressants offer alternatives when patients can't tolerate or don't respond to first-line agents (for example, bupropion is a good choice when sexual dysfunction from SSRIs is a concern).

Mood Stabilizer Indications

• Bipolar disorder is the primary indication, covering manic, hypomanic, depressive, and mixed episodes
• Treatment-resistant depression: Lithium is sometimes added to an antidepressant as an augmentation strategy
• Suicide risk reduction: Lithium has the strongest evidence for reducing suicidal behavior in bipolar patients
• Rapid-cycling bipolar disorder: Valproate and carbamazepine are often preferred over lithium
• Bipolar depression: Lamotrigine is particularly effective here
• Schizoaffective disorder: Mood stabilizers are sometimes used as adjunctive therapy

Adverse Effects and Drug Interactions

This is high-yield material. Know the side effect profiles by class:

• Antidepressants metabolized by cytochrome P450 enzymes (especially CYP2D6 and CYP3A4) can interact with many other medications. Fluoxetine and paroxetine are potent CYP2D6 inhibitors.
• MAOIs + serotonergic drugs (SSRIs, SNRIs, meperidine, tramadol) can trigger life-threatening serotonin syndrome. A washout period of at least 2 weeks is required when switching between MAOIs and other antidepressants (5 weeks for fluoxetine due to its long half-life).
• MAOIs + tyramine-rich foods can cause a hypertensive crisis because tyramine (normally broken down by MAO in the gut) enters the circulation and triggers massive norepinephrine release.
• Lithium levels are affected by drugs that alter renal sodium handling. NSAIDs, ACE inhibitors, and thiazide diuretics can all increase lithium levels and risk toxicity. Dehydration has the same effect.
• Carbamazepine induces CYP3A4 and other CYP enzymes, potentially reducing the effectiveness of oral contraceptives, warfarin, and many other drugs.