What are the first-line treatments for patients requiring psychopharmacological intervention for depression, bipolar disorder, and schizophrenia?

First-Line Psychopharmacological Treatments

For depression, start with second-generation antidepressants (SSRIs or SNRIs); for bipolar disorder, initiate lithium, valproate, or atypical antipsychotics; for schizophrenia, begin with an atypical antipsychotic selected based on side-effect profile through shared decision-making.

Depression

Second-generation antidepressants (SGAs) are the first-line pharmacological treatment for major depressive disorder. 1 This class includes:

• Selective serotonin reuptake inhibitors (SSRIs)
• Serotonin norepinephrine reuptake inhibitors (SNRIs)
• Bupropion, mirtazapine, nefazodone, and trazodone 1

SGAs are preferred over first-generation antidepressants (tricyclics and MAOIs) due to lower toxicity in overdose while maintaining similar efficacy. 1

Treatment phases to monitor:

• Acute phase: 6-12 weeks of dose optimization 1
• Continuation phase: 4-9 months to consolidate gains 1
• Maintenance phase: ≥1 year to prevent recurrence 1

Critical consideration for adolescents: The Treatment of Adolescent Depression Study demonstrated that combination therapy (medication + CBT) or medication management alone showed efficacy at 12 weeks, but CBT alone did not, suggesting that beginning with psychotherapy only in moderate to severe depression may not be optimal. 1

Bipolar Disorder

For acute mania, first-line agents include lithium, valproate, or atypical antipsychotics. 1 The choice should be based on:

1. Evidence of efficacy
2. Phase of illness (acute mania vs. maintenance)
3. Presence of psychotic symptoms or rapid cycling
4. Side-effect profile and safety
5. Patient/family medication history and preferences 1

FDA-approved agents by age:

• Lithium: Approved for ages ≥12 years for acute mania and maintenance 1
• Atypical antipsychotics: Aripiprazole, olanzapine, risperidone, quetiapine, and ziprasidone are approved for acute mania in adults 1
• Maintenance therapy: Lamotrigine and olanzapine approved in adults 1

Avoid antidepressant monotherapy as it may destabilize mood or precipitate manic episodes; if used for bipolar depression, always combine with a mood stabilizer. 1

Schizophrenia

Begin with an atypical antipsychotic selected collaboratively with the patient based on side-effect and efficacy profiles. 1 The distinction between first- and second-generation antipsychotics should not guide choice, as this classification lacks pharmacological or clinical validity. 1

Treatment algorithm:

1. First-line (Week 0-4): Start any atypical antipsychotic at therapeutic dose for minimum 4 weeks with good adherence 1

2. Second-line (Week 4-8): If significant positive symptoms persist, switch to an alternative antipsychotic with different pharmacodynamic profile. For patients who started with a D2 partial agonist, consider amisulpride, risperidone, paliperidone, or olanzapine (with samidorphan or concurrent metformin). 1

3. Third-line (Week 8+): If positive symptoms remain significant after second adequate trial, reassess diagnosis and contributing factors (substance use, organic illness), then initiate clozapine if schizophrenia confirmed. 1

Clozapine dosing specifics:

• Co-prescribe metformin to attenuate weight gain 1
• Titrate to plasma level ≥350 ng/mL 1
• If inadequate response at 12 weeks, increase to 350-550 ng/mL 1
• Levels >550 ng/mL have NNT=17 with increased seizure risk; consider prophylactic lamotrigine if pursuing higher levels 1

Pediatric considerations: For adolescents (13-17 years), risperidone demonstrated efficacy at 1-6 mg/day, with doses of 1-3 mg/day showing comparable efficacy to 4-6 mg/day, and no additional benefit above 3 mg/day. 2

Common pitfall: Clozapine is generally reserved for treatment-resistant cases (failure of ≥2 antipsychotics, at least one atypical) due to significant adverse effects including neutropenia and seizures, which may occur at higher rates in youth. 1