Second-Generation Antidepressants

Second-generation antidepressants include a heterogeneous group of compounds developed since the 1980s, which have progressively replaced tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) as the first-line treatment for major depressive disorder. Although their mechanisms of action differ, they share greater pharmacological selectivity and a lower incidence of side effects compared to first-generation antidepressants.

The common denominator of these drugs is the modulation of monoaminergic transmission — primarily serotonin (5-HT), norepinephrine (NE), and dopamine (DA) — achieved through selective reuptake inhibition, specific receptor blockade, or synergistic multimodal action. These properties allow for a more personalized therapeutic approach, tailored to the patient’s clinical and symptomatic profile.

All second-generation antidepressants require low-dose initiation and gradual titration, with a clinical response latency generally between 2 and 4 weeks. Treatment should be maintained for at least 6–12 months following remission to reduce the risk of relapse, and may continue longer in cases of recurrent depression.

Classification

Second-generation antidepressants are divided into several subclasses based on their mechanism of action:

• SSRIs (Selective Serotonin Reuptake Inhibitors): fluoxetine, sertraline, escitalopram, citalopram, paroxetine, fluvoxamine;
• SNRIs (Serotonin-Norepinephrine Reuptake Inhibitors): venlafaxine, desvenlafaxine, duloxetine, milnacipran;
• NaSSAs (Noradrenergic and Specific Serotonergic Antidepressants): mirtazapine;
• NDRIs (Norepinephrine-Dopamine Reuptake Inhibitors): bupropion;
• SARIs (Serotonin Antagonists and Reuptake Inhibitors): trazodone;
• Multimodal serotonergic modulators: vortioxetine, vilazodone;
• Agomelatine: melatonergic MT1/MT2 receptor agonist and 5-HT2C antagonist.

Each subclass presents unique pharmacodynamic and pharmacokinetic features that influence therapeutic choice, clinical response, and individual tolerability.

SSRIs – Selective Serotonin Reuptake Inhibitors

SSRIs (Selective Serotonin Reuptake Inhibitors) represent the most widely used class in the treatment of major depressive disorder and are generally considered the first-line pharmacological option according to international guidelines. Their mechanism of action involves selective inhibition of the serotonin transporter (SERT), leading to increased synaptic concentrations of 5-HT and enhanced stimulation of various postsynaptic receptors. Although receptor modulation occurs rapidly, clinical effects emerge after 2–4 weeks, a timeframe needed for neuroadaptive changes.

This class includes: fluoxetine, sertraline, escitalopram, citalopram, paroxetine, and fluvoxamine. Despite sharing the same basic mechanism, each molecule has a unique pharmacokinetic and receptor-binding profile, which affects therapeutic selection based on the patient’s individual characteristics.

Clinically, SSRIs are indicated not only for unipolar major depression, but also for various comorbid disorders such as generalized anxiety disorder, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder, and bulimia nervosa. They are generally well tolerated, have low toxicity in overdose, and their pharmacological profile makes them suitable for outpatient and long-term use.

The most common side effects are related to peripheral serotonergic stimulation: nausea, headache, insomnia, diarrhea or constipation, and decreased libido or anorgasmia. In most cases, these symptoms are transient and subside within the first weeks of treatment. However, in some patients, they may persist and affect adherence.

Among the available SSRIs, certain clinical differences may guide selection:

• Sertraline: balanced profile, also effective in post-stroke or post-myocardial infarction depression; may cause mild gastrointestinal side effects;
• Escitalopram: high selectivity for SERT, excellent tolerability, low risk of drug interactions;
• Fluoxetine: long half-life, suitable for younger or non-adherent patients; may cause activation or insomnia;
• Paroxetine: marked anticholinergic and sedative effect; not recommended for elderly or metabolically vulnerable patients;
• Fluvoxamine: also approved for obsessive-compulsive disorder, with strong anxiolytic effect but numerous CYP450 interactions.

SSRI selection should be based on the symptomatic profile, pharmacological history, metabolic status, and the presence of comorbidities. In case of poor response, dosage may be increased within approved limits or a switch to another SSRI or a different class may be considered.

Treatment discontinuation should always be gradual to avoid withdrawal symptoms, particularly with short half-life agents like paroxetine. Fluoxetine, on the other hand, can be stopped more flexibly due to its long half-life and active metabolites.

SNRIs – Serotonin-Norepinephrine Reuptake Inhibitors

SNRIs (Serotonin-Norepinephrine Reuptake Inhibitors) represent a significant evolution from SSRIs, as they inhibit both the serotonin transporter (SERT) and the norepinephrine transporter (NET). This dual action makes them particularly suitable for depression characterized by anergia, apathy, psychomotor retardation, or when a prominent pain component is present. The main active agents in this class include venlafaxine, desvenlafaxine, duloxetine, and milnacipran.

Due to their noradrenergic stimulation, SNRIs have an activating profile, with energizing effects that may initially increase anxiety, especially in agitated or anxious patients. Venlafaxine, for example, exhibits a biphasic action: serotonergic inhibition predominates at low doses, while norepinephrine reuptake inhibition becomes more significant at doses above 150 mg/day.

Clinically, in addition to major depressive disorder, SNRIs are approved for generalized anxiety disorder, panic disorder, and especially for neuropathic pain and fibromyalgia, where duloxetine is often considered a first-line option.

Side effects are similar to those seen with SSRIs but also include dose-dependent hypertension (notably with venlafaxine), tachycardia, and at times insomnia, agitation, and excessive sweating. Blood pressure monitoring is advised, especially in patients with a cardiovascular history. Sexual dysfunction is common but varies between compounds.

Some practical guidance for drug selection:

• Duloxetine: effective in depression with somatic or neuropathic pain, such as fibromyalgia or diabetic neuropathy;
• Venlafaxine: useful for apathetic patients with anhedonia, psychomotor slowing, or SSRI-resistant depression;
• Desvenlafaxine: active metabolite of venlafaxine, with more stable plasma levels and lower interindividual variability;
• Milnacipran (not approved for psychiatric use in Italy): used in other countries for fibromyalgia and depression, with a pronounced activating profile.

As with SSRIs, SNRIs should be tapered gradually. Venlafaxine in particular is known for a high risk of withdrawal syndrome, characterized by dizziness, paresthesias, restlessness, sleep disturbances, and mood swings. Discontinuation should be slow and carefully monitored.

NaSSA – Mirtazapine

Mirtazapine is the only clinically relevant representative of the NaSSA class (Noradrenergic and Specific Serotonergic Antidepressants). It has a unique mechanism of action: it functions as a presynaptic alpha-2 adrenergic antagonist, enhancing the release of norepinephrine and serotonin, and as a selective antagonist of 5-HT2 and 5-HT3 serotonin receptors, thereby boosting serotonergic transmission through the 5-HT1A receptor, which is implicated in antidepressant effects.

This combined mechanism gives mirtazapine a distinct pharmacological profile, with marked sedative, anxiolytic, and orexigenic properties. It is particularly helpful in patients with depression associated with severe insomnia, weight loss, fatigue, or anxious agitation.

It is administered as a single evening dose. At lower doses (15–30 mg), its sedative effect predominates due to H1 receptor antagonism, while at higher doses (30–45 mg), noradrenergic activation becomes more prominent. This makes mirtazapine a “dose-dependent” drug in terms of its clinical effect.

The most frequent side effects include increased appetite, weight gain, and significant sedation, which can be therapeutically beneficial in selected patients. It is well tolerated in terms of sexual and gastrointestinal side effects. Routine blood tests or ECG monitoring are generally not required during treatment.

NDRIs – Bupropion

Bupropion belongs to the NDRI class (Norepinephrine-Dopamine Reuptake Inhibitors) and has an atypical pharmacological profile. It inhibits the reuptake of norepinephrine and dopamine but does not affect serotonin reuptake. The result is a predominantly activating and stimulating clinical effect, useful in patients presenting with symptoms such as anergia, psychomotor retardation, apathy, and cognitive sluggishness.

Bupropion is particularly suitable for patients who experience sexual side effects with SSRIs, as it is generally neutral—or even beneficial—in that regard. It is also widely used as an aid for smoking cessation, due to its action on the mesolimbic dopaminergic system.

Although well tolerated overall, bupropion is not free of risks. It may cause restlessness, insomnia, tremor, headache, and, most importantly, lowers the seizure threshold. For this reason, it is contraindicated in patients with a history of epilepsy, eating disorders (anorexia or bulimia), or those taking other medications that increase seizure risk.

It should be taken in the morning or early afternoon to minimize sleep disturbances. The effective dosage typically ranges from 150 to 300 mg/day. It is available in modified-release formulations that improve convenience and adherence.

SARIs – Trazodone

Trazodone belongs to the SARI class (Serotonin Antagonist and Reuptake Inhibitor). It acts through a dual mechanism: moderate inhibition of the serotonin transporter (SERT), combined with selective blockade of 5-HT2A and 5-HT2C receptors, which are implicated in many of the adverse effects associated with SSRIs. This combination grants trazodone both antidepressant and prominent sedative-anxiolytic properties.

Trazodone is frequently prescribed for depression associated with refractory insomnia or strong anxious components. At sub-antidepressant doses (25–150 mg), it is mainly used for sleep induction, while full antidepressant effects require doses above 300–400 mg/day, which may increase the incidence of side effects.

Besides sedation, trazodone may cause orthostatic hypotension, daytime drowsiness, and rarely, priapism. It is generally well tolerated at the gastrointestinal level and does not cause significant sexual dysfunction, making it a good option for sensitive patients.

Multimodal serotonergic modulators: vortioxetine and vilazodone

Multimodal serotonergic modulators, including vortioxetine and vilazodone, represent one of the latest pharmacological developments in depression treatment. These drugs combine serotonin reuptake inhibition with action on specific 5-HT receptor subtypes, yielding broader and more targeted clinical effects.

Vortioxetine, approved for major depressive disorder, inhibits SERT and modulates several serotonin receptors: partial agonist at 5-HT1A, antagonist at 5-HT3, 5-HT1D, and 5-HT7. In addition to its antidepressant effect, it appears to have documented cognitive benefits, making it particularly suitable for patients with attention, memory, or concentration deficits. It is well tolerated, with a low incidence of sexual dysfunction and weight gain.

Vilazodone, not currently available in Italy, combines SERT inhibition with partial agonism at the 5-HT1A receptor. It has demonstrated antidepressant efficacy and good sexual tolerability, although it must be taken with food to ensure optimal absorption.

Agomelatine

Agomelatine is an atypical antidepressant that acts outside the classical monoaminergic system. It is an agonist of melatonergic MT1 and MT2 receptors and a 5-HT2C antagonist. Its primary action is the restoration of circadian rhythms, which are often disrupted in depressed patients, leading to improvements in sleep quality, daytime energy, and mood regulation.

Agomelatine is indicated in patients with circadian rhythm disturbances, insomnia, persistent fatigue, or depressive symptoms associated with altered chronotype. It has no sexual side effects and does not induce weight gain. However, it requires regular hepatic monitoring (liver enzymes before initiation and every 6 weeks), due to the rare but potential risk of hepatotoxicity.

The recommended dose is 25 mg/day, taken in the evening. In cases of partial response, the dose may be increased to 50 mg/day.

Final Considerations

Second-generation antidepressants offer a wide range of therapeutic possibilities, adaptable to the various clinical forms of depression and to the individual profiles of patients. Their improved tolerability compared to classical antidepressants has made them the standard in modern clinical practice.

The choice of active ingredient must be individualized, taking into account the patient's symptom profile, medical or psychiatric comorbidities, prior treatment response, and tolerability. Within this context, the most effective approach remains an integrated one, combining pharmacotherapy with psychological, psychoeducational, and functional support interventions.

Ongoing clinical monitoring, clear communication, and active patient engagement are the pillars of an antidepressant therapy that is effective, sustainable, and oriented toward full functional and relational recovery.

Summary Table

References
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