Navigating Effexor Withdrawal: Better Approaches To Tapering

Overview  

• Venlafaxine (Effexor, Effexor XR) is a serotonin-noradrenaline reuptake inhibitor (SNRI), with its major targets being the serotonin transporter (SERT) and the noradrenaline transport (NET) 
• Used in adults for the treatment of major depressive disorder, generalized anxiety disorder, social anxiety disorder, and panic disorder
• Venlafaxine is extensively metabolized to its active metabolite O-desmethylvenlafaxine (ODV)
• The half-life of venlafaxine is roughly 5 hours, while its active metabolite ODV has a half-life of roughly 11 hours. This means it takes 5 hours for the body to use up half of the venlafaxine and 22 hours to use up half of ODV. So after approximately 10 hours the body should have fully used up venlafaxine and about 44 hours have processed the active metabolite ODV. 
• Given the variation in drug plasma levels it is not recommended to use every other day dosing. It is extremely important that people who are using immediate release venlafaxine take their medication 2-3 times a day to maintain steady drug levels due to the short half life
• Peak plasma of immediate release venlafaxine and its metabolite ODV is 2 and 3 hours respectively. This means that the peak effect of the medicine should be experienced about 2-3 hours after taking the medication 

Side Effects of Venlafaxine

The following information is taken from the FDA approved documentation on the common and rare but serious side effects found through short term studies of the drug.

Venlafaxine Withdrawal Symptoms

• In a trial of venlafaxine given for 8 weeks, 71% (44/62) of patients met the criteria for a withdrawal syndrome after a brief two week taper. This study only followed up people for two weeks after stopping. 1 After 8 weeks of medication use, 38.7% of patients were judged to be moderately severe, 3.2% to be severe and 1.6% to be very severe. Severe effects are likely to be more common after longer-term use. (References 3-5)  
• Venlafaxine is considered to have a moderate risk of causing withdrawal syndrome when the drug is discontinued or decreased in dosage 

Some commonly reported withdrawal effects when discontinuing venlafaxine can be found below. It should be noted that there are a variety of other withdrawal symptoms that can be experienced by an individual including the following:

Interested in learning more about withdrawal symptoms? Check out this resource.

Tapering Venlafaxine

• At Outro, we utilize a hyperbolic approach to tapering. This means making smaller and smaller changes in a dose as the dose decreases. This reduces the likelihood of developing intense withdrawal symptoms. If you are interested in learning more about hyperbolic tapering, check out this resource.
• If venlafaxine is stopped abruptly (ie. cold turkey) or over a few weeks, there is a potential to develop withdrawal symptoms which can range in time and severity from mild and brief to severe and long lasting
• Making small dose reductions according to this “hyperbolic” pattern lets the body adapt to “the new normal” level of serotonin. Instead of jumping from the top of the stairs, small steps are taken until we safely reach the bottom of the staircase. 

The relationship between the dose of venlafaxine and occupancy of its major targets, the serotonin transporter (SERT) and noradrenaline transport (NET) is hyperbolic. Dose reductions made by linear amounts (e.g. 300mg, 150mg, 75mg, 37.5mg, 0mg) will cause increasingly-sized reductions in effect, which may cause increasingly severe withdrawal effects. To produce an equally-sized reduction in effect on the brain will require hyperbolically reducing doses, which informs the reductions presented by the healthcare providers at Outro. 

Creating A Venlafaxine Taper Plan 

• Creating a taper plan is something that a person should do in collaboration with a healthcare practitioner. Balancing both the physiological needs - meaning crafting the plan to be in line with the changes occurring in the brain and body, while also paying close attention to the individual's circumstances and response to the taper.
• Before implementing a plan, predicting the risk of withdrawal may be helpful to be able to prepare for the road ahead.
• Utilizing custom dose sizes and formulations (through compounding pharmacies, or other methods) will help individuals to taper off of venlafaxine in a safer way compared to traditional linear tapers 
• Monitoring symptoms during the taper is extremely important as the development of withdrawal symptoms can be a clue into determining if the rate of taper is too quick. Tell your healthcare provider about any side effects that develop and how severe they are being experienced. The goal is to minimize symptoms to the best of our abilities, white knuckling through symptoms is generally not recommended here at Outro. Sometimes that involves having to slightly increase the dose and change the rate of the taper. 
• Allowing enough time in between dose reductions is critically important when creating a tapering plan. Giving the body enough time to stabilize and adjust to the new normal is essential. Generally 2-4 weeks at minimum may be of benefit. Avoiding the layering of withdrawal symptoms by allowing the body to return to its “normal” state prior to tapering before making any further changes is key! 

Sample Taper Plan

To give you an idea of what a taper plan might look like see the below image taken from the Royal College of Psychiatrists. This plan outlines a “fast tapering schedule” for citalopram (not venlafaxine) and should not be confused or taken as medical advice - this is purely an example. Recall that each person should meet with a healthcare provider to determine the risk of withdrawal in order to plan appropriately paced and reduced taper schedule. Many individuals will not be able to taper an antidepressant as fast as the example provided below.

Clinical Support Tapering Venlafaxine

Ceasing the use of venlafaxine (Effexor) should always be done under the guidance of a healthcare professional who specializes in tapering antidepressants.

The tapering process varies for each person, and taper plans should be customized based on the individual's response and medical history.

The tapering process varies for each person, and taper plans should be customized based on the individual's response and medical history. It’s essential to closely monitor and manage withdrawal symptoms with the help of a healthcare provider, adjusting the plan as necessary. One common issue is the availability of smaller dose sizes, which often requires cooperation with a compounding pharmacy to ensure accurate dosing during the tapering process.

The development of a science-based approach like hyperbolic tapering is a positive step towards improving the process of discontinuing antidepressants like venlafaxine (Effexor), and much more work is needed to close this last mile in mental health medication.

References

1. Venlafaxine 37.5 mg tablets. https://www.medicines.org.uk/emc/product/773/smpc (accessed Oct 15, 2022).
2. Food and Drug Administration. Reference ID: 4036390 - Label for Effexor.. Retrieved March 3, 2023, from https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020699s107lbl.pdf 
3. Henssler J, Heinz A, Brandt L, Bschor T. Antidepressant Withdrawal and Rebound Phenomena. Dtsch Arztebl Int 2019; 116: 355–61.
4. Horowitz MA, Framer A, Hengartner MP, Sorensen A, Taylor DM. Estimating risk of withdrawal from a review of published data (Accepted - CNS Drugs). 2022.
5. Quilichini J-B, Revet A, Garcia P, et al. Comparative effects of 15 antidepressants on the risk of withdrawal syndrome: A real-world study using the WHO pharmacovigilance database. J Affect Disord 2021; 297: 189–93.
6. Sir A, D’Souza RF, Uguz S, et al. Randomized trial of sertraline versus venlafaxine XR in major depression: Efficacy and discontinuation symptoms. J Clin Psychiatry 2005; 66: 1312–20.
7. Sørensen A, Ruhé HG, Munkholm K. The relationship between dose and serotonin transporter occupancy of antidepressants—a systematic review. Mol Psychiatry 2021; : 1–10.
8. Holford N. Pharmacodynamic principles and the time course of delayed and cumulative drug effects. Translational and Clinical Pharmacology 2018; 26: 56–56.
9. Furukawa TA, Cipriani A, Cowen PJ, Leucht S, Egger M, Salanti G. Optimal dose of selective serotonin reuptake inhibitors, venlafaxine, and mirtazapine in major depression: a systematic review and dose-response meta-analysis. The Lancet Psychiatry 2019; 6: 601–9.
10. Horowitz MA, Taylor D. Tapering of SSRI treatment to mitigate withdrawal symptoms. The Lancet Psychiatry 2019; 6: 538–46.
11. Venlafaxine 75mg/5ml Oral Solution. https://www.medicines.org.uk/emc/product/12750/smpc (accessed Oct 15, 2022).
12. Pfizer. Label for Effexor XR (venlafaxine Extended-Release) Capsules. 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020699s107lbl.pdf.
13. Institute for Safe Medication Practices. Institute for Safe Medication Practices. Institute for Safe Medication Practices. https://www.ismp.org/ (accessed Oct 10, 2022).
14. Groot PC, van Os J. How user knowledge of psychotropic drug withdrawal resulted in the development of person-specific tapering medication. Therapeutic Advances in Psychopharmacology 2020; 10: 204512532093245
15. Stopping antidepressants: Royal College of Psychiatrists. www.rcpsych.ac.uk. (n.d.). Retrieved April 5, 2023, from https://www.rcpsych.ac.uk/mental-health/treatments-and-wellbeing/stopping-antidepressants 

‍