In a middle‑aged adult with hypothyroidism, generalized anxiety disorder, systemic lupus erythematosus, and bipolar disorder (moderate depressive episode) currently taking cariprazine 3 mg, hydroxychloroquine 200 mg, ibuprofen 800 mg as needed, levothyroxine 100 µg, lovastatin 40 mg, and venlafaxine extended‑release 37.5 mg started last month, who reports severe depression and anxiety (9/10) and sleeps only five hours per night, what medication change should be made?

Increase Venlafaxine Dose and Optimize Thyroid Management

The most critical intervention is to increase venlafaxine from 37.5 mg to 150 mg daily (the therapeutic dose), while simultaneously verifying that levothyroxine 100 µg achieves euthyroid status, since untreated or undertreated hypothyroidism directly causes treatment-resistant depression and anxiety. 1, 2, 3

Immediate Medication Adjustments

Venlafaxine Dose Escalation

• The current dose of 37.5 mg is subtherapeutic—this is a starting dose, not a treatment dose, explaining why depression and anxiety remain at 9/10 after one month. 1
• Increase to 75 mg daily for 4–7 days, then advance to 150 mg daily if tolerated. 1
• The therapeutic range for major depressive disorder is 150–225 mg daily; most patients require at least 150 mg to achieve remission. 1
• Allow 6–8 weeks at the therapeutic dose (≥150 mg) before concluding the trial is inadequate. 4, 5

Critical Thyroid Assessment Required

• Order TSH, free T4, and thyroid antibodies (anti-TPO, anti-thyroglobulin) immediately—hypothyroidism is a leading cause of treatment-resistant depression and anxiety, and this patient's levothyroxine dose may be insufficient. 4, 2, 3, 6
• Untreated or undertreated hypothyroidism causes depressive symptoms, anxiety, fatigue, and insomnia that will not respond to antidepressants alone. 2, 3, 6
• Elevated TSH or thyroid antibodies are independently associated with depression, anxiety, and increased suicide risk even when free T4 is normal. 4, 6
• If TSH is elevated (>2.5–3.0 mIU/L in a patient with psychiatric symptoms), increase levothyroxine by 12.5–25 µg and recheck in 6 weeks. 2

Bipolar Disorder Safety Considerations

Cariprazine as Mood Stabilizer

• Cariprazine 3 mg provides adequate mood stabilization for bipolar depression, allowing safe continuation of venlafaxine. 7
• The patient is already on a therapeutic dose of an atypical antipsychotic with FDA approval for bipolar disorder, satisfying the requirement for mood stabilizer coverage before using an antidepressant. 7

Monitoring for Mood Destabilization

• Assess weekly for the first month after each venlafaxine dose increase for signs of hypomania or mania: decreased need for sleep, increased energy, racing thoughts, impulsivity, or irritability. 7, 1
• The FDA black-box warning for antidepressants in bipolar disorder emphasizes that screening and mood stabilizer co-treatment are essential to prevent manic switches. 1

Sleep Intervention

Immediate Sleep Hygiene

• The 5-hour sleep duration is both a symptom of inadequate treatment and a perpetuating factor for depression and anxiety. 1
• Venlafaxine can cause insomnia in 15–20% of patients; if insomnia worsens after dose escalation, add trazodone 50–100 mg at bedtime. 1

Thyroid-Related Sleep Disruption

• Hypothyroidism commonly causes both hypersomnia and non-restorative sleep; optimizing thyroid replacement often improves sleep quality within 2–4 weeks. 2, 3

Monitoring Timeline

Week 1–2 After Dose Increase

• Assess for suicidal ideation, agitation, unusual behavioral changes, and manic symptoms—the highest risk period for antidepressant-related adverse events. 1
• Monitor blood pressure and heart rate, as venlafaxine can cause sustained hypertension (mean increase 7.2 mm Hg at higher doses). 1

Week 4–6

• Recheck thyroid function tests if TSH was abnormal at baseline. 2
• Assess partial response: energy, sleep, appetite, and concentration typically improve before mood. 1

Week 6–8

• Formal efficacy assessment at therapeutic venlafaxine dose (≥150 mg) and optimized thyroid status. 4, 1
• If depression/anxiety scores remain ≥7/10, consider augmentation with bupropion or switching to a different SNRI. 4, 5

Critical Pitfalls to Avoid

• Do not add bupropion or another antidepressant until venlafaxine reaches 150 mg for 6–8 weeks—premature polypharmacy obscures which intervention is effective. 4, 5
• Do not overlook thyroid optimization—even subclinical hypothyroidism (TSH 2.5–10 mIU/L with normal free T4) causes treatment-resistant depression. 4, 2, 6
• Do not mistake early activation or anxiety from venlafaxine dose escalation for bipolar mania—transient restlessness in the first 1–2 weeks is common and resolves with continued treatment. 1
• Do not stop cariprazine—discontinuing the mood stabilizer while escalating an antidepressant significantly increases manic switch risk in bipolar disorder. 7

Systemic Lupus Erythematosus Considerations

• Hydroxychloroquine 200 mg daily is appropriate maintenance therapy and does not interact with venlafaxine or levothyroxine. 4
• If new neuropsychiatric symptoms emerge (confusion, hallucinations, severe headache), obtain urgent brain MRI and CSF analysis to exclude CNS lupus, which can mimic treatment-resistant depression. 4
• Corticosteroid-induced psychiatric symptoms occur in 10% of patients on prednisone ≥1 mg/kg; this patient is not on corticosteroids, so this is not a concern. 4