What medications can be taken with Zoloft (sertraline) for depression?

Medications That Can Be Taken With Zoloft (Sertraline) for Depression

Cognitive Behavioral Therapy (CBT) combined with sertraline is the preferred treatment approach for depression and anxiety disorders, showing superior outcomes to medication alone. 1

Safe Medication Combinations

Psychotherapy (First-Line Augmentation)

• CBT plus sertraline demonstrates moderate evidence for improved response rates, remission, and global function compared to sertraline monotherapy 1
• This combination is particularly effective for social anxiety, generalized anxiety, separation anxiety, and panic disorder in patients 6-18 years old 1

Other Antidepressants (Use With Extreme Caution)

When sertraline alone is insufficient, switching to alternative second-generation antidepressants may be considered:

• Bupropion (Wellbutrin), extended-release venlafaxine, or other SSRIs can be used as alternatives when switching medications, with approximately 25% of patients achieving symptom-free status after switching 1
• However, combining sertraline with other serotonergic antidepressants (SSRIs, SNRIs, TCAs) significantly increases serotonin syndrome risk and requires extreme caution 1

Medications Requiring Dose Adjustment

• Tricyclic antidepressants (TCAs): Sertraline inhibits CYP2D6 metabolism, potentially increasing TCA plasma levels by substantial amounts 1, 2, 3
  • TCA doses must be reduced when co-administered with sertraline 2
  • Plasma TCA monitoring is recommended 2
  • Sertraline's effect on TCAs may be less profound than fluoxetine, fluvoxamine, or paroxetine 3

Absolutely Contraindicated Combinations

MAOIs (Monoamine Oxidase Inhibitors)

Never combine sertraline with MAOIs - this is absolutely contraindicated due to life-threatening serotonin syndrome risk 1, 2

• Includes phenelzine, isocarboxazid, moclobemide, isoniazid, and linezolid 1
• Requires 2-week washout period when switching between sertraline and MAOIs 2

Other High-Risk Combinations

Avoid or use extreme caution with:

• Pimozide (Orap): Absolutely contraindicated due to serious cardiac effects 2
• Disulfiram (Antabuse): Contraindicated with liquid sertraline formulations due to alcohol content 2

Medications Requiring Monitoring for Serotonin Syndrome

When combining sertraline with the following serotonergic drugs, start at low doses, increase slowly, and monitor intensively for 24-48 hours after any dose change: 1

Pain Medications

• Tramadol, meperidine, methadone, fentanyl 1, 2

Migraine Medications

• Triptans (sumatriptan, etc.) - monitor for weakness, hyperreflexia, incoordination 2

Stimulants

• Amphetamines and possibly methylphenidate 1

Over-the-Counter Products

• Dextromethorphan (cough suppressant) 1
• St. John's Wort 1, 2
• L-tryptophan 1, 2

Other Psychiatric Medications

• Lithium 2
• Buspirone 2

Medications With Bleeding Risk

NSAIDs (ibuprofen, naproxen) and aspirin increase bleeding risk when combined with sertraline 1, 2

• Odds ratio 1.2-1.5 for gastrointestinal bleeding 1
• Risk is higher with concurrent antiplatelet or NSAID use 1

Medications With Minimal Interaction Concerns

Cardiovascular Medications

• Atenolol: No interaction with sertraline 2
• Digoxin: No change in serum levels or renal clearance 2
• Warfarin: Monitor INR closely but can be co-administered 2

Diabetes Medications

• Tolbutamide: Sertraline causes 16% decrease in clearance, but clinical significance unknown 2
• Monitor blood glucose when initiating combination 2

Cardiac Medications

Propafenone and flecainide: Sertraline may increase plasma concentrations via CYP2D6 inhibition 1, 2

• These drugs have narrow therapeutic indices and require dose reduction 2

Critical Serotonin Syndrome Warning Signs

Seek immediate emergency care if these symptoms develop: 1, 2

• Mental status changes: confusion, agitation, hallucinations, delirium, coma 2
• Neuromuscular symptoms: tremor, rigidity, myoclonus, hyperreflexia, incoordination 2
• Autonomic instability: tachycardia, labile blood pressure, hyperthermia, diaphoresis 2
• Advanced symptoms: fever, seizures, arrhythmias, unconsciousness 1

Treatment requires immediate discontinuation of all serotonergic agents and hospital-based supportive care with continuous cardiac monitoring 1

Key Clinical Pearls

• Sertraline has relatively lower CYP450 inhibition compared to other SSRIs (especially fluoxetine, paroxetine, fluvoxamine), resulting in fewer drug-drug interactions 1, 4
• Sertraline does not significantly inhibit CYP3A4, as demonstrated by lack of interaction with terfenadine, carbamazepine, and cisapride 2
• When augmentation is needed, prioritize CBT over adding additional medications 1
• If switching antidepressants, allow appropriate washout periods, particularly when transitioning to/from MAOIs 2