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Good Info for Nolvadex And Antidepressant Mixtures!!

tubesox

tubesox

Member
10+ Year Member
Choosing among antidepressants while using Nolvadex(tamoxifen) for PCT:

Antidepressants vary in their ability to inhibit CYP2D6 (the enzyme that converts tamoxifen into its active form, endoxifen).

Drug
Effect on CYP2D6
Advice

venlafaxine (Effexor)
Minimal
Safest choice if taken with (Nolvadex) tamoxifen.

desvenlafaxine (Pristiq), mirtazapine (Remeron)
Direct studies with tamoxifen are lacking, but effect on endoxifen levels should be minimal.
citalopram (Celexa), escitalopram (Lexapro), nefazodone (Serzone)
Mild
Secondary choices if above are not options.

Only citalopram and sertraline have been studied directly with tamoxifen, so risk of reducing levels of endoxifen should be weighed against benefits of antidepressants.

duloxetine (Cymbalta), sertraline (Zoloft), fluvoxamine (Luvox)
Moderate

paroxetine (Paxil), fluoxetine (Prozac), bupropion (Wellbutrin)
Strong
Best to avoid if taking tamoxifen

http://www.health.harvard.edu/newsletters/Harvard_Mental_Health_Letter/2010/June/antidepressants-and-tamoxifen
 
Good post, I keep Nolva on hand but I use Clomid PCT. If for some reason the AI craps out and I start growing teets I will run the Nolva.
 
[Open Access] Tamoxifen and Potent CYP2D6 Inhibitors

Tamoxifen has a well-established role in the management of oestrogen-receptor positive breast cancer halving the 5-year recurrence risk of early stage breast cancer, reducing mortality and controlling metastasis.

It is an inactive pro-drug which is activated by the hepatic cytochrome P450 system. The most important of metabolites are 4-hydroxytamoxifen and 4-hydroxy-N-desmethyltamoxifen (endoxifen). Both metabolites have a 100-fold greater affinity for the oestrogen receptor compared to tamoxifen.

Endoxifen is the most pharmacologically active metabolite. This conversion is by cytochrome P450 isoenzyme 2D6 (CYP2D6). The CYP2D6 gene located on chromosome 22 is highly polymorphic with more than 80 different major alleles identified.

Many alleles confer decreased or absent CYP2D6 activity. Reduced activity leads to lower endoxifen concentrations, increased risk of breast cancer recurrence and a shorter time to cancer relapse. Although conflicting data exist, these studies suggest an important role for CYP2D6 activity in tamoxifen metabolism.

Co-administration of tamoxifen with medications that inhibit the activity of CYP2D6 can reduce endoxifen formation reducing tamoxifen effectiveness. This has major implications for clinical practice. Up to 25% of breast cancer patients experience clinically significant depression.

CYP2D6 inhibitors selective serotonin reuptake inhibitor (SSRI) and norepinephrine reuptake inhibitor (SNRI) antidepressants are used as initial therapies. They are also used to treat tamoxifen-associated hot flushes.

The potent SSRIs paroxetine and fluoxetine have a significant effect on tamoxifen metabolism. Paroxetine is the only SSRI that exhibits suicide inhibition with irreversible loss of enzyme function. Sertraline and citalopram are moderate inhibitors of CYP2D6. Venlafaxine escitalopram and mirtazepine are considered to have little or no inhibition of CYP2D6.

A retrospective investigation of the long-term impact of CYP2D6 inhibitors on clinical outcomes in 24,430 women treated for breast cancer with tamoxifen over a 13-year period, reported that 30% received at least one concomitant antidepressant.

Paroxetine was most commonly prescribed (25%). Breast cancer related death rates were significantly higher in women in this cohort. This risk was directly proportional to the duration of co-prescribing. Such studies have resulted in recommendations to avoid potent CYP2D6-inhibiting antidepressants in patients receiving tamoxifen.

Despite this, records from a community pharmacy database of three million people in the Netherlands demonstrated that paroxetine remains one of the most frequently prescribed antidepressants in women receiving tamoxifen. Prescribing trends matched those of the general population.

An Irish study utilising the Primary Care Reimbursement Services pharmacy database, identified 4526 women commenced on tamoxifen between2001 and 2006 4 . Thirteen percent (n=599) were co-prescribed tamoxifen with moderate (6.9%) or potent (7.6%) CYP2D6 inhibitors. In 5.8% of patients, the CYP2D6 inhibitor was started after tamoxifen. While more recent co-prescription rates have fallen, we remain concerned about the lack of awareness of this interaction.

Paroxetine and fluoxetine co-administration with tamoxifen should be avoided. Preference should be given to antidepressants that show little or no inhibition of CYP2D6 such as venlafaxine and escitalopram. When the use of a potent CYP2D6 inhibitor is considered necessary, co-administration should be limited to the shortest possible duration.

Battley JE, O'Connor M, Barron TI, O'Reilly S. Tamoxifen and Potent CYP2D6 Inhibitors: A Potentially Lethal Interaction. Ir Med J. 2015;108(6):188-9. http://www.lenus.ie/hse/handle/10147/558639
 
Damn. I take Wellbutrin. One of the articles mentioned that paxil causes irreversible inhibition of the enzyme needed for tamox. I wonder now about Wellbutrin and what that could mean even if I were to come off of it.
 
Michael Scally MD said:
[Open Access] Tamoxifen and Potent CYP2D6 Inhibitors

Tamoxifen has a well-established role in the management of oestrogen-receptor positive breast cancer halving the 5-year recurrence risk of early stage breast cancer, reducing mortality and controlling metastasis.

It is an inactive pro-drug which is activated by the hepatic cytochrome P450 system. The most important of metabolites are 4-hydroxytamoxifen and 4-hydroxy-N-desmethyltamoxifen (endoxifen). Both metabolites have a 100-fold greater affinity for the oestrogen receptor compared to tamoxifen.

Endoxifen is the most pharmacologically active metabolite. This conversion is by cytochrome P450 isoenzyme 2D6 (CYP2D6). The CYP2D6 gene located on chromosome 22 is highly polymorphic with more than 80 different major alleles identified.

Many alleles confer decreased or absent CYP2D6 activity. Reduced activity leads to lower endoxifen concentrations, increased risk of breast cancer recurrence and a shorter time to cancer relapse. Although conflicting data exist, these studies suggest an important role for CYP2D6 activity in tamoxifen metabolism.

Co-administration of tamoxifen with medications that inhibit the activity of CYP2D6 can reduce endoxifen formation reducing tamoxifen effectiveness. This has major implications for clinical practice. Up to 25% of breast cancer patients experience clinically significant depression.

CYP2D6 inhibitors selective serotonin reuptake inhibitor (SSRI) and norepinephrine reuptake inhibitor (SNRI) antidepressants are used as initial therapies. They are also used to treat tamoxifen-associated hot flushes.

The potent SSRIs paroxetine and fluoxetine have a significant effect on tamoxifen metabolism. Paroxetine is the only SSRI that exhibits suicide inhibition with irreversible loss of enzyme function. Sertraline and citalopram are moderate inhibitors of CYP2D6. Venlafaxine escitalopram and mirtazepine are considered to have little or no inhibition of CYP2D6.

A retrospective investigation of the long-term impact of CYP2D6 inhibitors on clinical outcomes in 24,430 women treated for breast cancer with tamoxifen over a 13-year period, reported that 30% received at least one concomitant antidepressant.

Paroxetine was most commonly prescribed (25%). Breast cancer related death rates were significantly higher in women in this cohort. This risk was directly proportional to the duration of co-prescribing. Such studies have resulted in recommendations to avoid potent CYP2D6-inhibiting antidepressants in patients receiving tamoxifen.

Despite this, records from a community pharmacy database of three million people in the Netherlands demonstrated that paroxetine remains one of the most frequently prescribed antidepressants in women receiving tamoxifen. Prescribing trends matched those of the general population.

An Irish study utilising the Primary Care Reimbursement Services pharmacy database, identified 4526 women commenced on tamoxifen between2001 and 2006 4 . Thirteen percent (n=599) were co-prescribed tamoxifen with moderate (6.9%) or potent (7.6%) CYP2D6 inhibitors. In 5.8% of patients, the CYP2D6 inhibitor was started after tamoxifen. While more recent co-prescription rates have fallen, we remain concerned about the lack of awareness of this interaction.

Paroxetine and fluoxetine co-administration with tamoxifen should be avoided. Preference should be given to antidepressants that show little or no inhibition of CYP2D6 such as venlafaxine and escitalopram. When the use of a potent CYP2D6 inhibitor is considered necessary, co-administration should be limited to the shortest possible duration.

Battley JE, O'Connor M, Barron TI, O'Reilly S. Tamoxifen and Potent CYP2D6 Inhibitors: A Potentially Lethal Interaction. Ir Med J. 2015;108(6):188-9. http://www.lenus.ie/hse/handle/10147/558639
Click to expand...
Dr. Scally, do you think upping tamoxifen dosage will offset the interference from a drug such as bupropion? Or would going from 20 to 40 mg nolva be equally useless in your opinion? Thanks.
 
Secret of Steel said:
Dr. Scally, do you think upping tamoxifen dosage will offset the interference from a drug such as bupropion? Or would going from 20 to 40 mg nolva be equally useless in your opinion? Thanks.
Click to expand...

!) Offset the interference? I suppose that means will a higher dose of Tamoxifen interfere with the effectivenss of antidepressants such as Buproban........ NO!

2) Would increasing the dose of Novla be equally useless? For what?

Sorry but it's hard to answer any question "correctly" when I don't know what the question is!
 
Hahaha, what I got out of it was...yeh, if you take higher dose will it be more effective or just useless?
 
USELESS for WHAT, as CNS treatment for PCT or as adjunctive antidepressant therapy?
OR as systemic therapy for the unwanted peripheral effects of E-2 such as bloat or gynecomastia ?

What may appear to be statistically or metabolically "significant" is NOT always clinically relevant. The post by Dr Scally acknowledges some 3 MILLION people have been using a Tamo/antidepressant combination that is seemingly contraindicated BUT where is the evidence this drug/drug interaction results in less effective therapy for either the depressed patient or those with breast CA?

Just a question and I've not investigated the answer YET, but as always thanks for the enlightening CME DOC
:)
:) :)
:) :) :)
 
Last edited:
Secret of Steel said:
Dr. Scally, do you think upping tamoxifen dosage will offset the interference from a drug such as bupropion? Or would going from 20 to 40 mg nolva be equally useless in your opinion? Thanks.
Click to expand...

Increasing the tamoxifen dosage has proven beneficial (increasing endoxifen concentrations) in cases involving genetic polymorphisms of CYP2D6, so it seems likely that it will also be beneficial in cases involving antidepressant inhibition of CYP2D6. YMMV


Breast. 2014 Aug;23(4):400-6.
Adjusting the dose of tamoxifen in patients with early breast cancer and CYP2D6 poor metabolizer phenotype.
Martinez de Dueñas E1, Ochoa Aranda E2, Blancas Lopez-Barajas I3, Ferrer Magdalena T2, Bandrés Moya F4, Chicharro García LM5, Gómez Capilla JA6, Zafra Ceres M7, de Haro T7, Romero Llorens R8, Ferrer Albiach C9, Ferriols Lisart R10, Chover Lara D8, López Rodríguez A8, Munárriz Ferrandis J8, Olmos Antón S8.

Abstract

BACKGROUND:
CYP2D6 is a key enzyme in tamoxifen metabolism, transforming it into its main active metabolite, endoxifen. Poor CYP2D6 metabolizers (PM) have lower endoxifen plasma concentrations and possibly benefit less from treatment with tamoxifen. We evaluated tamoxifen dose adjustment in CYP2D6 PM patients in order to obtain plasma concentrations of endoxifen comparable to patients with extensive CYP2D6 metabolism (EM).

PATIENTS AND METHODS:
Comprehensive CYP2D6 genotyping and plasma tamoxifen metabolite concentrations were performed among 249 breast cancer patients in adjuvant treatment with tamoxifen. Tamoxifen dose was increased in PM patients to 40 mg and to 60 mg daily for a 4-month period each, repeating tamoxifen metabolite measurements on completion of each dose increase. We compared the endoxifen levels between EM and PM patients, and among the PM patients at each dose level of tamoxifen (20, 40 and 60 mg).

RESULTS:
Eleven PM patients (4.7%) were identified. The mean baseline endoxifen concentration in EM patients (11.30 ng/ml) was higher compared to the PM patients (2.33 ng/ml; p < 0.001). In relation to the 20 mg dose, increasing the tamoxifen dose to 40 and 60 mg in PM patients significantly raised the endoxifen concentration to 8.38 ng/ml (OR 3.59; p = 0.013) and to 9.30 ng/ml (OR 3.99; p = 0.007), respectively. These concentrations were comparable to those observed in EM patients receiving 20 mg of tamoxifen (p = 0.13 and p = 0.64, respectively).

CONCLUSION:
In CYP2D6 PM patients, increasing the standard tamoxifen dose two-fold or three-fold raises endoxifen concentrations to levels similar to those of patients with EM phenotype.



Breast Cancer Res Treat. 2012 Jan;131(1):137-45.
Dose-adjustment study of tamoxifen based on CYP2D6 genotypes in Japanese breast cancer patients.
Kiyotani K1, Mushiroda T, Imamura CK, Tanigawara Y, Hosono N, Kubo M, Sasa M, Nakamura Y, Zembutsu H.

Abstract
CYP2D6 is a key enzyme responsible for the metabolism of tamoxifen to active metabolites, endoxifen, and 4-hydroxytamoxifen. The breast cancer patients who are heterozygous and homozygous for decreased-function and null alleles of CYP2D6 showed lower plasma concentrations of endoxifen and 4-hydroxytamoxifen compared to patients with homozygous-wild-type allele, resulting in worse clinical outcome in tamoxifen therapy. We recruited 98 Japanese breast cancer patients, who had been taking 20 mg of tamoxifen daily as adjuvant setting. For the patients who have one or no normal allele of CYP2D6, dosages of tamoxifen were increased to 30 and 40 mg/day, respectively. The plasma concentrations of tamoxifen and its metabolites were measured at 8 weeks after dose-adjustment using liquid chromatography-tandem mass spectrometry. Association between tamoxifen dose and the incidence of adverse events during the tamoxifen treatment was investigated. In the patients with CYP2D6*1/*10 and CYP2D6*10/*10, the mean plasma endoxifen levels after dose increase were 1.4- and 1.7-fold higher, respectively, than those before the increase (P < 0.001). These plasma concentrations of endoxifen achieved similar level of those in the CYP2D6*1/*1 patients receiving 20 mg/day of tamoxifen. Plasma 4-hydroxytamoxifen concentrations in the patients with CYP2D6*1/*10 and CYP2D6*10/*10 were also significantly increased to the similar levels of the CYP2D6*1/*1 patients according to the increasing tamoxifen dosages (P < 0.001). The incidence of adverse events was not significantly different between before and after dose adjustment. This study provides the evidence that dose adjustment is useful for the patients carrying CYP2D6*10 allele to maintain the effective endoxifen level.



J Clin Oncol. 2011 Aug 20;29(24):3232-9.
Genotype-guided tamoxifen dosing increases active metabolite exposure in women with reduced CYP2D6 metabolism: a multicenter study.
Irvin WJ Jr1, Walko CM, Weck KE, Ibrahim JG, Chiu WK, Dees EC, Moore SG, Olajide OA, Graham ML, Canale ST, Raab RE, Corso SW, Peppercorn JM, Anderson SM, Friedman KJ, Ogburn ET, Desta Z, Flockhart DA, McLeod HL, Evans JP, Carey LA.

Abstract

PURPOSE:
We examined the feasibility of using CYP2D6 genotyping to determine optimal tamoxifen dose and investigated whether the key active tamoxifen metabolite, endoxifen, could be increased by genotype-guided tamoxifen dosing in patients with intermediate CYP2D6 metabolism.

PATIENTS AND METHODS:
One hundred nineteen patients on tamoxifen 20 mg daily ≥ 4 months and not on any strong CYP2D6 inhibiting medications were assayed for CYP2D6 genotype and plasma tamoxifen metabolite concentrations. Patients found to be CYP2D6 extensive metabolizers (EM) remained on 20 mg and those found to be intermediate (IM) or poor (PM) metabolizers were increased to 40 mg daily. Eighty-nine evaluable patients had tamoxifen metabolite measurements repeated 4 months later.

RESULTS:
As expected, the median baseline endoxifen concentration was higher in EM (34.3 ng/mL) compared with either IM (18.5 ng/mL; P = .0045) or PM (4.2 ng/mL; P < .001). When the dose was increased from 20 mg to 40 mg in IM and PM patients, the endoxifen concentration rose significantly; in IM there was a median intrapatient change from baseline of +7.6 ng/mL (-0.6 to 23.9; P < .001), and in PM there was a change of +6.1 ng/mL (2.6 to 12.5; P = .020). After the dose increase, there was no longer a significant difference in endoxifen concentrations between EM and IM patients (P = .84); however, the PM endoxifen concentration was still significantly lower.

CONCLUSION:
This study demonstrates the feasibility of genotype-driven tamoxifen dosing and demonstrates that doubling the tamoxifen dose can increase endoxifen concentrations in IM and PM patients.
 
Oh I would not say it's useless but exclusive of the initial loading dose, I much prefer the lower dose of any SERM. That's bc IME, the adverse effects of SERMS increase on a disproportionate basis relative to the dose being used.

But really with respect to PCT the amount of SERMS needed is finite since the number of functional receptors a gland the size of a pea can possess is limited. To that end I think many OD on SERMs as PCT!
 
So to that end bc Buproban inhibits the conversion of Tamoxifen into its active form endoxifen what dosage adjustment should be made (if any) to ensure PCT is effective.

Now I understand the question!

And the answer is largely unknown, lol!

Can you tell me why it's unknown TS?

Because no one KNOWS what SERM dosage is required for PCT! Heck many folk recover HTPA functioning wo PCT, although the delay in that recovery is demonstrable in the majority IME.

i KNOW if it's anything like the NAC dosage used for TYLENOL OD patients, the amount of SERMS "needed" for PCT is far LESS than what is being used!

CBS what changes in the baseline concentrations were noted in the studies you reviewed?
 
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Dr JIM said:
CBS what changes in the baseline concentrations were noted in the studies you reviewed?
Click to expand...

The mean baseline endoxifen concentration in EM patients (11.30 ng/ml) was higher compared to the PM patients (2.33 ng/ml; p < 0.001). In relation to the 20 mg dose, increasing the tamoxifen dose to 40 and 60 mg in PM patients significantly raised the endoxifen concentration to 8.38 ng/ml (OR 3.59; p = 0.013) and to 9.30 ng/ml (OR 3.99; p = 0.007), respectively. These concentrations were comparable to those observed in EM patients receiving 20 mg of tamoxifen (p = 0.13 and p = 0.64, respectively).
 
Thanks CBS.

OK TS so from this data one might conclude CA patients being treated with Tamoxifen and antidepressants in either category would need to increase their Tamoxifen dose by 20-40 mg daily.

Well but that's not necessarily true bc we now need to correlate the efficacy of Tamoxifen with its serum concentration!

However bc the correlation of drug bound receptor mediated physiologic processes involve intracellular transduction of that drug/receptor to the nucleus, where subsequent commands are mediated, serum concentrations can be much less than ideal.

Nonetheless that's what we are stuck with. So next up, a midline search for studies that correlate endoxifen levels to its efficacy in CA or better yet gynecomastia patients.

I'll see what I can find tomorrow. Dr Scally if you're aware of such a study, any assistance is appreciated.
 
Dr JIM said:
Nonetheless that's what we are stuck with. So next up, a midline search for studies that correlate endoxifen levels to its efficacy in CA or better yet gynecomastia patients.

I'll see what I can find tomorrow. Dr Scally if you're aware of such a study, any assistance is appreciated.
Click to expand...

Madlensky et al identified an endoxifen threshold of 5.97 ng/ml (=16.0 nM).


Madlensky L1, Natarajan L, Tchu S, Pu M, Mortimer J, Flatt SW, Nikoloff DM, Hillman G, Fontecha MR, Lawrence HJ, Parker BA, Wu AH, Pierce JP.
Clin Pharmacol Ther. 2011 May;89(5):718-25.
Tamoxifen metabolite concentrations, CYP2D6 genotype, and breast cancer outcomes.


Abstract
We explored whether breast cancer outcomes are associated with endoxifen and other metabolites of tamoxifen and examined potential correlates of endoxifen concentration levels in serum including cytochrome P450 2D6 (CYP2D6) metabolizer phenotype and body mass index (BMI). Concentration levels of tamoxifen, endoxifen, 4-hydroxytamoxifen (4OH-tamoxifen), and N-desmethyltamoxifen (ND-tamoxifen) were measured from samples taken from 1,370 patients with estrogen receptor (ER)-positive breast cancer who were participating in the Women's Healthy Eating and Living (WHEL) Study. We tested these concentration levels for possible associations with breast cancer outcomes and found that breast cancer outcomes were not associated with the concentration levels of tamoxifen, 4-hydroxytamoxifen, and ND-tamoxifen. For endoxifen, a threshold was identified, with women in the upper four quintiles of endoxifen concentration appearing to have a 26% lower recurrence rate than women in the bottom quintile (hazard ratio (HR) = 0.74; 95% confidence interval (CI), (0.55-1.00)). The predictors of this higher-risk bottom quintile were poor/intermediate metabolizer genotype, higher BMI, and lower tamoxifen concentrations as compared with the mean for the cohort as a whole. This study suggests that there is a minimal concentration threshold above which endoxifen is effective against the recurrence of breast cancer and that ~80% of tamoxifen takers attain this threshold.
 
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