I have major depressive disorder, generalized anxiety disorder and panic disorder, and have been on venlafaxine XR 150 mg daily, gabapentin, hydroxyzine, propranolol as needed, occasional trazodone, and recently increased fluoxetine (Prozac) to 30 mg without improvement; I’m now experiencing more frequent mood swings and a worsening depressive tone—what should I do now before my next appointment?

Immediate Medication Management for Worsening Mood Swings and Depression

You should not be taking both venlafaxine (Effexor) 150 mg and fluoxetine (Prozac) 30 mg simultaneously—this combination significantly increases your risk of serotonin syndrome without proven efficacy benefit, and your worsening mood swings may be directly related to this unsafe polypharmacy. 1

Critical Safety Issue: Dangerous Drug Combination

Your current regimen includes both an SNRI (venlafaxine) and an SSRI (fluoxetine), which should never be combined:

• Combining venlafaxine with fluoxetine markedly raises the risk of serotonin syndrome (confusion, agitation, tremor, rapid heart rate, fever, muscle rigidity) without any demonstrated benefit over monotherapy 1
• This combination may be contributing to your worsening mood instability and increased mood swings 1
• Your prescriber needs to discontinue one of these medications immediately 1

Recommended Treatment Algorithm

Step 1: Optimize Your Venlafaxine Dose (Most Likely Solution)

The therapeutic dose range for venlafaxine XR is 150-225 mg daily, and you are currently at the minimum therapeutic dose 1:

• Many patients are prescribed sub-therapeutic venlafaxine doses; simply increasing to 225 mg daily often resolves worsening depressive symptoms 1
• Venlafaxine has demonstrated superior efficacy to SSRIs (including fluoxetine) for treatment-resistant depression and anxiety 1, 2
• Discontinue the fluoxetine completely and increase venlafaxine to 225 mg daily 1
• Allow 6-8 weeks at the optimized 225 mg dose before declaring treatment failure 1

Step 2: Add Cognitive-Behavioral Therapy Immediately

While optimizing your medication, you must start CBT now—combination therapy demonstrates superior efficacy compared to medication alone for both depression and anxiety 1:

• CBT can be initiated immediately while adjusting medication dose, providing synergistic benefit 1
• Individual CBT following structured protocols (Clark-and-Wells or Heimberg models) is first-line psychotherapy 1
• If face-to-face CBT is not accessible, structured self-help CBT programs with therapist support are evidence-based alternatives 1

Step 3: If Venlafaxine Optimization Fails After 8 Weeks

Consider bupropion SR augmentation (150-400 mg daily) rather than switching medications 1:

• Bupropion augmentation achieves remission rates of approximately 50% compared to 30% with SNRI monotherapy alone 1
• Bupropion has significantly lower discontinuation rates due to adverse events (12.5%) compared to buspirone (20.6%, p<0.001) 1
• Start bupropion SR at 150 mg daily and increase by 150 mg every 3-7 days as tolerated, with the second dose before 3 p.m. to reduce insomnia risk 1
• Do not use bupropion if you have any history of seizures or eating disorders 1

Critical Safety Monitoring

Suicidality Risk (Highest Priority)

• Antidepressant medicines may increase suicidal thoughts or actions in young adults within the first few months of treatment, especially after medication changes 3
• Your prescriber must assess for suicidal ideation at every contact during the first 1-2 months after any medication adjustment 1
• Call your healthcare provider immediately if you experience thoughts about suicide or dying, attempts to commit suicide, new or worse depression, new or worse anxiety, feeling very agitated or restless, panic attacks, trouble sleeping, new or worse irritability, acting aggressive or violent, or other unusual changes in behavior or mood 3

Serotonin Syndrome Warning Signs

Monitor yourself closely during the first 24-48 hours after any dose change for 1:

• Mental status changes (confusion, agitation)
• Neuromuscular hyperactivity (tremor, muscle rigidity, hyperreflexia)
• Autonomic symptoms (fever, rapid heart rate, sweating, dilated pupils)
• Seek emergency care immediately if these symptoms develop

Why Your Current Regimen Is Problematic

The Fluoxetine Addition Was Inappropriate

• You have been stable on venlafaxine 150 mg for nearly 6 years, which suggests it has been effective 4, 5
• Adding fluoxetine to venlafaxine creates a dangerous drug interaction without evidence of benefit 1
• Venlafaxine alone at optimized doses (150-225 mg) is more effective than fluoxetine for depression with anxiety, with remission rates of 37% vs 22% respectively 5, 2
• In head-to-head trials, venlafaxine demonstrated significantly greater efficacy than fluoxetine for reducing both depressive symptoms and concomitant anxiety 2

Your Mood Swings May Be Medication-Induced

• The worsening mood swings you describe coincide with the fluoxetine addition and dose increase 1
• Behavioral activation syndrome (increased agitation, anxiety, mood instability) can emerge within 24-48 hours of SSRI dose adjustments 1
• Removing the fluoxetine and optimizing venlafaxine alone may resolve these symptoms 1

Duration of Continuation Therapy

Given your long history of recurrent depression and anxiety (diagnosed at ages 10 and 15), you will likely require years to lifelong maintenance therapy 1:

• For patients with 2 or more episodes, longer duration therapy (years to lifelong) is recommended to prevent relapse 1
• After achieving remission, continue treatment for at least 4-9 months minimum, but likely indefinitely given your recurrent course 1

Common Pitfalls to Avoid

• Never stop venlafaxine suddenly—discontinuation syndrome causes dizziness, anxiety, irritability, and sensory disturbances 3
• Do not wait 2 more weeks for your appointment—contact your prescriber immediately about the unsafe venlafaxine-fluoxetine combination 1
• Do not switch to another SSRI—you need venlafaxine optimization or augmentation, not another SSRI trial 1
• Do not make medication changes more frequently than every 2-4 weeks—this prevents adequate assessment of response and increases destabilization risk 1

Your Adjunctive Medications Are Appropriate

Your current use of gabapentin, hydroxyzine, propranolol, and trazodone as adjuncts is reasonable 1:

• Hydroxyzine and venlafaxine both prolong QTc interval—ensure your prescriber monitors with baseline ECG if you have cardiac risk factors 1
• Trazodone 25 mg is appropriate for sleep but not for depression treatment (antidepressant doses are 50-400 mg daily) 1
• These adjuncts can continue while optimizing your primary antidepressant regimen 1