Antidepressants - Venlafaxine Withdrawal

Neuroleptic Nightmare
by Malcolm Hulatt

Avoiding Withdrawal Symptoms

Rapid elimination of some antidepressant medication, e.g. venlafaxine, can introduce feelings of being unwell some of which can be quite severe and lead to the reintroduction of the medication, not necessarily because of the need for the drug to treat the illness but because of a crisis precipitated by its dependency.

For venlafaxine these are flu like symptoms which pass after a week or two in a severe case. Both this and the rate of recovery will be dependent on:

  • the size of the reduction in terms of both the actual amount (mg) and in percentage terms
  • the usage/decay rate of the drug in the body
  • how long the drug has been taken.

The rate of reduction must be slow to avoid any withdrawal symptoms or relapse.

To do this effectively it is necessary to understand how long the drug remains in the body after being taken. The important factor is not the amount being taken but the level in the body at any one time. This is particularly important if different forms of the same drug are available.

Anti-depressant half-life

The length of time it takes a drug to be consumed or dissipated in the body is characterised by the half-life. If we assume that the drug is rapidly absorbed into the blood, the level will then start to fall over a period of time. When the amount has fallen to half the initial level achieved, this is referred to as the half-life usually measured in hours or days. Some drugs have a short half-life because the body rapidly assimilates them. This is like a sugar lump effect when it is dissolved in the mouth relatively quickly.

Taking a short half life tablet twice per day will lead to little accumulation in the body. Some drugs have a longer half-life and may remain in the body at significant concentrations for several days. This results in an accumulation of the drug in the body. Understanding this is particularly important where a medication like venlafaxine has more than one form. Changing from one form to another at the same dosage level can lead to major changes in body concentration and withdrawal problems.

Drug levels in the body

There is a standard tablet form of venlafaxine which has half-life of 8 to 10 hours. These figures are taken from the manufacturer’s web site. In practice the actual rate will depend on whether it is taken with food and the individual’s own metabolic rate but this is not critical to the process. Taken twice per day, a drug with a half-life of 9 hours will build to a level of 1.64 times the dosage assuming an exponential decay rate. Therefore a dosage of 75 mg twice per day roughly gives 123 mg in the body. This is made up of:

  • the dose of the new tablet 1.00
  • the remaining dose from 12 hours before 0.39
  • the remaining dose from 1 day before 0.16
  • the remaining dose from 1.5 days before 0.06
  • the remaining dose from 2.0 days before 0.02
  • the remaining dose from 2.5 days before 0.01

Total 1.64 x 75 mg = 123 mg.

The elimination of a tablet with a short half-life will have a more rapid reduction in the amount of the drug in the body than when a same sized (mg) longer half-life capsule is eliminated as described below.

There is also a venlafaxine XL capsule whose half-life is given as 22 to 24 hours. Assuming the same decay mechanism for the capsule as for the tablet, a half-life of 23 hours would build to a level of 3.27 times the dosage. Therefore a dosage of 75 mg twice per day roughly gives 246 mg in the body. This is made up of:

  • the dose of the new capsule 1.00
  • the remaining dose from 12 hours before 0.71
  • the remaining dose from 1 day before 0.49
  • the remaining dose from 1.5 days before 0.35
  • the remaining dose from 2.0 days before 0.24
  • the remaining dose from 2.5 days before 0.16
  • the remaining dose from 3.0 days before 0.11
  • the remaining dose from 3.5 days before 0.08
  • the remaining dose from 4.0 days before 0.06
  • the remaining dose from 4.5 days before 0.04
  • the remaining dose from 5.0 days before 0.02
  • the remaining dose from 5.5 days before 0.01

Total 3.27 x 75 mg = 245 mg.

The above numbers are not exact because of different metabolisation characteristics of the differing drug forms and the fact that the initial dose is not absorbed instantly. However, if they had the same release mechanism in principle the XL capsule variety would give roughly double the body concentration of the tablet for the same dose taken. In practice the modified release mechanism for the XL capsule results in the ratio being lower at more like 1.7 instead of 2.0. This means that the maximum dose for the drug is different depending on whether the patient is taking the capsule or the tablet form. In fact, in the drug handbook in the UK, MIMS (Monthly Index Of Medical Specialities) this difference in maximum levels is stipulated clearly showing the tablet maximum to be 375 mg and the capsule maximum to be 225 mg. This confirms the mechanism for the modified release capsule is not exponential. However the principle remains valid: the amount of drug in the body when taking the capsule is very significantly greater than when taking tablet form.

This was discovered by us after a consultant psychiatrist had arbitrarily changed the dose from 150 mg twice per day of XL capsule (way over the maximum) to 150 mg twice per day of tablet giving horrendous withdrawal problems over 2 weeks followed 3 months later by extreme nausea when he arbitrarily switched back to the XL variety at the same dose.

Using Prozac for withdrawal due to its longer half-life

There are web sites claiming that substituting Prozac for venlafaxine in the final stages provides a rate of reduction of antidepressant which gives the patient no withdrawal problems. This is because of the long half-life on Prozac (4 days and 8 days for its intermediary – see the note in Section 5). Therefore the level of the drug in the body falls slowly at a rate to which the body can adjust when a capsule is eliminated from the dose taken. Therefore this Prozac decay rate was used initially as a model to calculate how quickly to reduce the venlafaxine medication levels. The option of changing over to Prozac was considered but this would have introduced a new drug and a new learning curve. The Prozac web site states 7% of patients cannot metabolise the drug in which case the body concentration quickly grows. This was seen as potentially being exposed to an unnecessary risk if the reduction could be done safely in another way.