Effexor

Another day, another "antidepressant"

Welcome to The Frontier Psychiatrists. It’s a newsletter. This is another installment in my series of articles on medications and their history—a sassy prescribing guide from someone… who is moving on to neuromodulation as fast as humanly possible.

---

Venlafaxine, brand name “Effexor,” was approved by the FDA in 1993, and the extended-release version, Effexor XR, was approved in 1997.

INDICATIONS AND USAGE

Effexor (venlafaxine hydrochloride) is indicated for the treatment of major depressive disorder.

The efficacy of Effexor in the treatment of major depressive disorder was established in 6-week controlled trials of adult outpatients whose diagnoses corresponded most closely to the DSM­ III or DSM-III-R category of major depression and in a 4-week controlled trial of inpatients meeting diagnostic criteria for major depression with melancholia (see CLINICAL TRIALS).

The molecule looks like this:

(For the Organic Chemistry Enthusiasts in the room).

Effexor is metabolized in the liver into its active metabolite, desvenlafaxine. You can now also be prescribed this as Pristiq. Without too much of a digression, hepatic (aka Liver) metabolism matters because, especially for a drug like Effexor, which is made more active by this metabolic process, the variability in the population of humans in how they process any drug matters. The liver has a series of proteins called enzymes, and they are called the cytochrome p450 family. They convert a drug into another molecule. That next molecule is either more or less active in the body than the parent compound. Effexor is processed at the 2D6 enzyme, which has a wide range of variability in humans. There are papers on the 2d6 genetics you have¹ predicting if this medicine will be helpful to you.

Some people process it slowly. Some people clear it out fast. You can't know in advance without a genetic test that didn’t exist in 1993 or 1997—and is still not in common use.

Venlafaxine was very exciting to psychopharmacologists—those physicians who were seduced by Sackler-style marketing to abandon psychiatry for “prescribing”—because it had a somewhat different mechanism of action. We heard about SSRIs—selective for serotonin, despite that not really mattering²—but this was differently selective for another monoamine, norepinephrine!

Paid consultants to, and employees of, the manufacturer of Venlafaxine wrote papers claiming it was better than the competing SSRIs in a meta-analyses³:

Results

Remission rates were: venlafaxine, 45%; SSRIs, 35%; placebo, 25%, favoring venlafaxine v. SSRIs p > 0001, OR 1.5). The difference between venlafaxine and the SSRIs was significant at week 2, whereas the difference between SSRIs and placebo reached significance at week 4. Results were not dependent on any one study or the definition of remission.

Conclusions

Remission rates were significantly higher with venlafaxine than with an SSRI.

A much more careful meta-analysis by the inimitable Dr. Nemeroff, a very careful academic in my opinion, was much more guarded:

These results indicate that venlafaxine therapy is statistically superior to SSRIs as a class, but only to fluoxetine individually. The clinical significance of this modest advantage seems limited for the broad grouping of major depressive disorder. Nonetheless, an NNT of 17 may be of public health relevance given the large number of patients treated for depression and the significant burden of illness associated with this disorder.⁴

And fans—like myself—of pointing out sources of bias will note that Effexor is a more potent drug—maybe—for working and for sucking to take, as the dropout data hints at:

Attrition rates due to adverse events were higher with venlafaxine than with SSRI therapy, 11% and 9% respectively (p = .0011).

A decade later, this gem was highlighted by meta-analysis enthusiasts in 2005:

In the past decade, no new or unexpected adverse events have been identified with venlafaxine therapy, except a possibly greater risk of fatal overdose compared with other serotonergic drugs, suggesting the need for caution in patients with suicidal ideation.

Effexor, it’s just MORE, you know?

The adverse effects are notable— and are my real point. Generally, I’d be the kind of person to applaud more toxic and more effective drugs that did something, anything. My general take is that we need to balance risk and benefits— and that seems like what we are seeing above with Effexor.

I am midway through a love letter to clozapine, for heaven’s sake!

However, my issue with this (maybe) more effective oral antidepressant is not about whether it’s more effective (probably) and more toxic (probably) than a whole class of relatively milquetost compounds like Prozac, Zoloft, and Paxil.

My problem? It is what happens when you prescribe a drug as a physician—ideally deciding with your patient—that will have consequences that both of you will be ill-prepared to manage if things go exactly as can be foreseen.

What happens if you need to stop taking Effexor, ever?

This can happen by either choice or by chance. Anyone can lose a pill bottle. Or need to travel. Or forget a refill. Or get sick and not be able to swallow a pill. Or wake up the next day after a regular interval for other people—remember the variable genetics above? And… be in withdrawal.

One can find themselves unable to continue taking a pill— or choose to discontinue it. The big problem, in my mind, is Effexor has a “now what” that is particularly punitive:

Serious withdrawal symptoms may occur within hours of cessation or reduction of the usual dosage and may affect motor and coordination skills to such a degree that patients should be explicitly urged either to adhere to a strict medication routine or not to drive a car.⁵

In some cases, that can be just the next day if you forget one dose (continuing from the 2005 paper by Campagne, cited above):

However, little mention is found of the possibly severe effects of abrupt discontinuation or postponing ingestion of the daily dose for as little as 8 to 12 hours. Although a patient may have established that taking the drug does not noticeably affect the ability to drive a car or operate machinery, taking the drug in the evening if it is usually taken in the morning or forgetting to take the daily dose just once may induce sudden and severe disturbances in physical and mental condition that most definitely can impair normal functioning.

These can be prolonged effects, lasting 3-4 weeks or much, much longer. They can be very severe:

Withdrawal symptoms in some patients can be disabling and may make tapering and cessation extremely difficult. Venlafaxine is arguably the most common cause of severe withdrawal symptoms among modern antidepressants, even when tapered⁶⁷. Whether patients suffer significant withdrawal from venlafaxine seems independent of dosage,⁸ indications for use, length of treatment⁹, or taper duration.¹⁰

It might suck no matter what— and no matter how careful the physician and patient were in its prescribing. Further:

The most frequently reported adverse symptoms of tapering or stopping venlafaxine are nausea, vertigo, irritability, and lethargy¹¹¹²¹³

It also gets worse than that, with a very severe withdrawal phenomenon including:

• visual disturbances¹⁴

• Unpleasant physical sensations¹⁵

• Sensations, including the now famously awful “brain shocks.”¹⁶

• motor problems¹⁷

• cataplexy¹⁸¹⁹

• delirium²⁰

• mania²¹²²²³

• and, not to be left out, psychosis²⁴

Aside from being awful, these symptoms may be mistaken for other problems and medical conditions. They lead to unnecessary tests and treatment. It can force patients to continue a medication that could have been discontinued otherwise.

Which—come to think of it— sounds like a best-selling drug…

Oh, wait.

When they use the slogan, “Expect More,” here, at least, is truth in advertising.

1. Lobello, K. W., Preskorn, S. H., Guico-Pabia, C. J., Jiang, Q., Paul, J., Nichols, A. I., ... & Ninan, P. T. (2010). Cytochrome P450 2D6 phenotype predicts antidepressant efficacy of venlafaxine: a secondary analysis of 4 studies in major depressive disorder. The Journal of clinical psychiatry, 71(11), 4011.

2. Jaggar M, Banerjee T, Weisstaub N, Gingrich JA, Vaidya VA. 5-HT_2Areceptor loss does not alter acute fluoxetine-induced anxiety and exhibit sex-dependent regulation of cortical immediate early gene expression. Neuronal Signal. 2019 Feb 1;3(1):NS20180205. doi: 10.1042/NS20180205. PMID: 32714597; PMCID: PMC7363295.

3. Thase, M. E., Entsuah, A. R., & Rudolph, R. L. (2001). Remission rates during treatment with venlafaxine or selective serotonin reuptake inhibitors. The British journal of psychiatry, 178(3), 234-241.

4. Nemeroff, C. B., Entsuah, R., Benattia, I., Demitrack, M., Sloan, D. M., & Thase, M. E. (2008). Comprehensive Analysis of Remission (COMPARE) with Venlafaxine versus SSRIs. Biological Psychiatry, 63(4), 424-434. https://doi.org/10.1016/j.biopsych.2007.06.027

5. Campagne DM. Venlafaxine and serious withdrawal symptoms: warning to drivers. MedGenMed. 2005 Jul 6;7(3):22. PMID: 16369248; PMCID: PMC1681629.

6. Taylor D, Stewart S, Connolly A. Antidepressant withdrawal symptoms: telephone calls to a national medication helpline. J Affect Disord. 2006;95(1-3):129-133. PubMed doi:10.1016/j.jad.2006.04.026

7. Trenque T, Piednoir D, Frances C, et al. Reports of withdrawal syndrome with the use of SSRIs: a case/non-case study in the French Pharmacovigilance database. Pharmacoepidemiol Drug Saf. 2002;11(4):281-283. PubMeddoi:10.1002/pds.704

8. Campagne DM. Venlafaxine and serious withdrawal symptoms: warning to drivers. MedGenMed. 2005;7(3):22.

9. Baldwin DS, Montgomery SA, Nil R, et al. Discontinuation symptoms in depression and anxiety disorders. Int J Neuropsychopharmacol. 2007;10(1):73-84. PubMed doi:10.1017/S1461145705006358

10. Tint A, Haddad PM, Anderson IM. The effect of rate of antidepressant tapering on the incidence of discontinuation symptoms: a randomised study. J Psychopharmacol. 2008;22(3):330-332. PubMed doi:10.1177/0269881107081550

11. Rosenbaum JF, Zajecka J. Clinical management of antidepressant discontinuation. J Clin Psychiatry. 1997;58(suppl 7):37-40. PubMed

12. Parker G, Blennerhassett J. Withdrawal reactions associated with venlafaxine. Aust N Z J Psychiatry. 1998;32(2):291-294. PubMeddoi:10.3109/00048679809062742

13. Johnson H, Bouman WP, Lawton J. Withdrawal reaction associated with venlafaxine. BMJ. 1998;317(7161):787. PubMed doi:10.1136/bmj.317.7161.787a

14. Spindler PE. Palinopsia following discontinuation of venlafaxine. Psychiatr Prax. 2008;35(5):255- 257.

15. Kotzalidis GD, de Pisa E, Patrizi B, et al. Similar discontinuation symptoms for withdrawal from medium-dose paroxetine and venlafaxine after nine years in the same patient. J Psychopharmacol. 2008;22(5):581-584. PubMeddoi:10.1177/0269881107081562

16. Reeves RR, Mack JE, Beddingfield JJ. Shock-like sensations during venlafaxine withdrawal. Pharmacotherapy. 2003;23(5):678-681. PubMeddoi:10.1592/phco.23.5.678.32198

17. Haddad PM, Devarajan S, Dursun SM. Antidepressant discontinuation (withdrawal) symptoms presenting as ‘ stroke.’ J Psychopharmacol. 2001;15(2):139-141. PubMed doi:10.1177/026988110101500210

18. Wang J, Greenberg H. Status cataplecticus precipitated by abrupt withdrawal of venlafaxine. J Clin Sleep Med. 2013;9(7):715-716.

19. Nissen C, Feige B, Nofzinger E, et al. Transient narcolepsy-cataplexy syndrome after discontinuation of the antidepressant venlafaxine. J Sleep Res. 2005;14(2):207-208. PubMed doi:10.1111/j.1365-2869.2005.00447.x

20. van Noorden MS, Vergouwen AC, Koerselman GF. Delirium during withdrawal of venlafaxine. Ned Tijdschr Geneeskd. 2002;146(26):1236-1237. PubMed

21. Kora K, Kaplan P. Hypomania/mania induced by cessation of antidepressant drugs. Turk Psikiyatr Derg. 2008;19(3):329-333.

22. Khazaal Y. Mania after venlafaxine withdrawal in a patient with generalized anxiety disorder. Ann Pharmacother. 2007;41(2):359-360. PubMeddoi:10.1345/aph.1H504

23. Fava GA, Mangelli L. Mania associated with venlafaxine discontinuation. Int J Neuropsychopharmacol. 2003;6(1):89-90. PubMeddoi:10.1017/S1461145703003274

24. Koga M, Kodaka F, Miyata H, et al. Symptoms of delusion: the effects of discontinuation of low-dose venlafaxine. Acta Psychiatr Scand. 2009;120(4):329-331. PubMed doi:10.1111/j.1600-0447.2009.01433.x