What are the latest group of antidepressants and their salient features?

Latest Antidepressants and Their Salient Features

Second-Generation Antidepressants Remain the Current Standard

The "latest" group of antidepressants are the second-generation agents, which include SSRIs (selective serotonin reuptake inhibitors), SNRIs (serotonin-norepinephrine reuptake inhibitors), and atypical agents like bupropion and mirtazapine—these have replaced first-generation drugs (tricyclics and MAOIs) due to similar efficacy but significantly lower toxicity in overdose. 1, 2

Key Second-Generation Antidepressants

The 12 primary second-generation antidepressants evaluated in major guidelines include: 1

• SSRIs: fluoxetine, paroxetine, sertraline, citalopram, escitalopram, fluvoxamine
• SNRIs: venlafaxine, duloxetine
• Atypical agents: bupropion, mirtazapine, trazodone, nefazodone

Salient Features of Second-Generation Antidepressants

Efficacy Profile

• All second-generation antidepressants demonstrate equivalent efficacy for treating major depressive disorder—no single agent consistently outperforms others in head-to-head trials. 1

• Efficacy is similar across demographic subgroups including elderly patients (>65 years), different sexes, and various racial/ethnic groups. 1

• Only approximately one-third of patients achieve remission with initial antidepressant treatment, highlighting the need for augmentation strategies. 3, 4

Adverse Effect Differentiation

Since efficacy is equivalent, selection should be based on adverse effect profiles: 1

• Nausea/vomiting: Venlafaxine has higher incidence than other SSRIs 1

• Diarrhea: Sertraline causes more diarrhea than bupropion, citalopram, fluoxetine, fluvoxamine, mirtazapine, nefazodone, paroxetine, or venlafaxine 1

• Weight gain: Mirtazapine and paroxetine cause more weight gain than sertraline, trazodone, or venlafaxine 1

• Sedation: Trazodone produces more somnolence than bupropion, fluoxetine, mirtazapine, paroxetine, or venlafaxine 1

• Sexual dysfunction: Bupropion has significantly lower rates of sexual adverse events compared to fluoxetine or sertraline 1

• Cognitive effects: Paroxetine should be avoided when cognitive symptoms are prominent due to anticholinergic effects 5

Specific Clinical Scenarios

For depression with cognitive symptoms ("brain fog"): 5

• First choice: Bupropion—has the lowest rate of cognitive side effects and activating properties that improve concentration
• Second choice: SNRIs (venlafaxine or duloxetine)—the noradrenergic component may enhance attention
• Avoid: Paroxetine (anticholinergic effects worsen cognition)

For depression with insomnia: 1

• Escitalopram shows superiority over citalopram
• Nefazodone superior to fluoxetine
• Trazodone superior to both fluoxetine and venlafaxine

For depression with anxiety: 1

• No significant differences among fluoxetine, paroxetine, sertraline, bupropion, venlafaxine, citalopram, mirtazapine, or nefazodone

For depression with pain: 1

• Duloxetine and paroxetine show no significant differences in pain relief

Pharmacogenetic Considerations

CYP2D6 and CYP2C19 genetic testing can guide dosing for specific antidepressants: 1

• Fluoxetine and paroxetine are primarily metabolized through CYP2D6, which exhibits genetic variation
• Poor metabolizers may require dose adjustments to avoid toxicity
• Extensive metabolizers may require higher doses for adequate response

Newest Development: Atypical Antipsychotics as Adjunctive Therapy

FDA-Approved Augmentation Agents

The most recent advancement in antidepressant therapy is FDA approval of atypical antipsychotics for treatment-resistant depression: 4, 6

• Aripiprazole (approved 2007)—first FDA-approved adjunctive treatment 3, 6
• Quetiapine extended-release (approved 2009) 3, 6
• Olanzapine-fluoxetine combination (approved 2009) 3, 6
• Brexpiprazole (approved 2015)—indicated as adjunctive therapy to antidepressants for MDD in adults 7
• Cariprazine—approved for adjunctive treatment 4

Key Features of Atypical Antipsychotics for Depression

Critical dosing principle: These agents are effective for depression only at subantipsychotic doses—full antipsychotic doses are dysphorogenic and worsen depression. 6

Efficacy considerations: 4

• Multiple acute-phase studies demonstrate efficacy in improving depressive symptoms
• Clinically meaningful remission remains limited
• Should be reserved for patients who fail to respond to at least one alternative treatment strategy 8

Significant adverse effects: 4

• Weight gain
• Metabolic dysfunction (hyperglycemia, dyslipidemia)
• Extrapyramidal symptoms
• Tardive dyskinesia risk with long-term use
• Pathological gambling and compulsive behaviors 7

Black box warnings for brexpiprazole: 7

• Increased mortality in elderly patients with dementia-related psychosis
• Increased risk of suicidal thoughts and behaviors in pediatric and young adult patients

Dosing for Brexpiprazole (Example)

For major depressive disorder as adjunctive therapy: 7

• Starting dose: 0.5-1 mg/day
• Target dose: 2 mg/day
• Maximum dose: 3 mg/day
• Dose adjustments required for hepatic impairment, renal impairment (CrCl <60 mL/min), and CYP2D6 poor metabolizers

Treatment Algorithm

Initial treatment: 1

1. Select a second-generation antidepressant based on adverse effect profile, cost, and patient preference
2. Assess response within 1-2 weeks of initiation
3. If inadequate response at 6-8 weeks, modify treatment (switch or augment)

Duration of therapy: 1, 5

• Continue for 4-9 months after satisfactory response for first episode
• Longer duration (potentially indefinite) for patients with ≥2 episodes

For treatment-resistant depression: 8, 4

• Try at least one alternative antidepressant before considering augmentation with atypical antipsychotics
• If using atypical antipsychotics, frequently reassess safety and efficacy
• Use shared decision-making given significant metabolic and neurological risks

Common Pitfalls

• Assuming all second-generation antidepressants are identical—while efficacy is similar, adverse effect profiles differ substantially and should guide selection 1

• Using full antipsychotic doses for depression—subantipsychotic doses are required; higher doses worsen depression 6

• Premature augmentation—atypical antipsychotics should not be first-line; try switching antidepressants first 8

• Ignoring metabolic monitoring—patients on atypical antipsychotics require regular monitoring of weight, glucose, and lipids 4

• Inadequate treatment duration—stopping antidepressants before 4-9 months increases relapse risk 1, 5