Anxiety

[DaisyJayne1]

My husband has PV Jak2, intolerant to Hydroxyuria, and is to start Jakafi 10mg twice daily. He has severe anxiety and is on SSRI (duloxetine) with recent request to increase dose to 40mg. My concern is that both drugs use the same enzyme (CYP3A4) to metabolize both medications, meaning there will be competition for the availability of that enzyme, potentially reducing the effectiveness of one or both. What do others on Jakafi take with severe anxiety?

[welshhuw]

Hi DaisyJayne, maybe discuss your concerns with your medical team, I'm sure they would be happy to advise. As I'm sure you are aware, CYP3A4 is responsible for the metabolism of more than 50% of medicines, the liver and small intestine having significant CYP3A4 activity. If I understand correctly, as an enzyme Cytochrome P450 3A4 acts as a 'catalyser' and hence is not 'used up' as such. In terms of reducing the effectiveness of the drugs you mentioned, this is generally more likely to occur with CYP3A4 induction. To my knowledge neither drugs are in the categories that lead to CYP3A4 induction or inhibition. In addition, I didn't come across any drug-drug interaction data between these two drugs that could potential impact CYP3A4 induction/inhibition.

[DaisyJayne1 in reply to welshhuw]

Thank you for your reply! I did hear back from the pharmacist on the team today, and I was incorrect on thinking Duloxetine was SSRI... it is an NSSRI, so no contraindication as you stated. Thanks again!

[EPguy]

I meet the criteria you note re Rux and anxiety. (See my post "Last Dose" for why)

I've managed without SSRIs so far. But on interactions, this report has a comment:

"Enzyme inhibition occurs when 2 drugs sharing metabolism via the same isozyme compete for the same enzyme receptor site. The more potent inhibitor will predominate, resulting in decreased metabolism of the competing drug. For most drugs, this can lead to increased serum levels of the unmetabolized entity, leading to a greater potential for toxicity."

ncbi.nlm.nih.gov/pmc/articl...

Implication is one of the drugs will be impaired. The more precise solution suggested here is to monitor serum levels of each drug; these two drugs don't normally have that done. Another is whether each drug is working on reasonable or common doses. If so then maybe the CYP3A4 effect is not harmful. These are questions to discuss with Drs.

Interesting they note that grapefruit juice, the no go on Rux, can allow reduced dosing, but too unpredictable. There are other drugs that allow reduced doses of CYP3A4 metabolized drugs. Could be interesting when drug cost is a problem.

Is IFN an option?

--

I take Silexan lavender which has a marginal effect. Also very low dose (0.25mg) klonopin and very low dose Mirtazapine nightly. But I could end up on SSRI or SNRI, and your observation is helpful. For acute episodes I use a lavender spray in a cloth and sniff, it takes the edge off

There is a procedure, Transcranial magnetic stimulation (TMS) that can help anxiety. I tried it and had a bad outcome. Turns out there is a "depression protocol" and an anxiety one. Insurance pays for the former but I now know it may be hazardous for anxiety. I am considering trying the proper one as it seemed helpful the one session I had.

[DaisyJayne1 in reply to EPguy]

Thank you for your insight and links! As I stated in an earlier reply, I was incorrect in thinking Duloxetine was an SSRI, it's not. It's a SNRI and no contraindication.

[EPguy in reply to DaisyJayne1]

Anyway it is a good opportunity to be aware of these issues. Always need to be alert to the Grapefruit curse. I do miss the fruit.

[hunter5582]

You are asking a good question regarding a potential drug interaction. This is something we should all double check before combining any medications. It sounds like you have an awareness of the importance of how drugs are metabolized and potential adverse reactions.

Duloxetine is a Serotonin-Norepinephrine Reuptake Inhibitor (SNRI) . Medications that serotonin reuptake inhibitors (SRI), SSRIs and SNRIs, come with a potential bleeding risk since serotonin reuptake is involved in platelets forming clots. You are correct that duloxetine is metabolized in the liver extensively; CYP450: 1A2, 2D6 substrate. I have not seen evidence that there would be any competition for the CYP450 enzyme resulting in an issue with efficacy. There may be other issues, however.

Here is some information that may help. Note, it is good idea to check more than one source.

One site, ePocrates.com shows no interaction between Jakafi and duloxetine. It does however show an interaction with aspirin.

Monitor/Modify Tx duloxetine + aspirin monitor bleeding s/sx: combo may incr. risk of GI or other bleeding, incl. life-threatening (additive effects, antiplatelet effects augmented by inhibition of platelet serotonin uptake)

Drugs.com does show potential interactions.

Applies to: duloxetine, Jakafi (ruxolitinib)

MONITOR: Serotonin reuptake inhibitors (SRIs) may potentiate the risk of bleeding in patients treated with ulcerogenic agents and agents that affect hemostasis such as anticoagulants, platelet inhibitors, thrombin inhibitors, thrombolytic agents, or agents that commonly cause thrombocytopenia. The tricyclic antidepressant, clomipramine, is also a strong SRI and may interact similarly. Serotonin release by platelets plays an important role in hemostasis, thus SRIs may alter platelet function and induce bleeding. Published case reports have documented the occurrence of bleeding episodes in patients treated with psychotropic agents that interfere with serotonin reuptake. Bleeding events related to SRIs have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages. Additional epidemiological studies have confirmed the association between use of these agents and the occurrence of upper gastrointestinal bleeding, and concurrent use of NSAIDs or aspirin was found to potentiate the risk. Preliminary data also suggest that there may be a pharmacodynamic interaction between SSRIs and oral anticoagulants that can cause an increased bleeding diathesis. Concomitant administration of paroxetine and warfarin, specifically, has been associated with an increased frequency of bleeding without apparent changes in the disposition of either drug or changes in the prothrombin time. Bleeding has also been reported with fluoxetine and warfarin, while citalopram and sertraline have been reported to prolong the prothrombin time of patients taking warfarin by about 5% to 8%. In the RE-LY study (Randomized Evaluation of Long-term anticoagulant therapy), SRIs were associated with an increased risk of bleeding in all treatment groups.

MANAGEMENT: Caution is advised if SRIs or clomipramine are used in combination with other drugs that affect hemostasis. Close clinical and laboratory observation for hematologic complications is recommended. Patients should be advised to promptly report any signs of bleeding to their physician, including pain, swelling, headache, dizziness, weakness, prolonged bleeding from cuts, increased menstrual flow, vaginal bleeding, nosebleeds, bleeding of gums from brushing, unusual bleeding or bruising, red or brown urine, or red or black stools.

Applies to: Low Dose ASA (aspirin), duloxetine

MONITOR: Serotonin reuptake inhibitors (SRIs) may potentiate the risk of bleeding in patients treated with ulcerogenic agents and agents that affect hemostasis such as anticoagulants, platelet inhibitors, thrombin inhibitors, thrombolytic agents, or agents that commonly cause thrombocytopenia. The tricyclic antidepressant, clomipramine, is also a strong SRI and may interact similarly. Serotonin release by platelets plays an important role in hemostasis, thus SRIs may alter platelet function and induce bleeding. Published case reports have documented the occurrence of bleeding episodes in patients treated with psychotropic agents that interfere with serotonin reuptake. Bleeding events related to SRIs have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages. Additional epidemiological studies have confirmed the association between use of these agents and the occurrence of upper gastrointestinal bleeding, and concurrent use of NSAIDs or aspirin was found to potentiate the risk. Preliminary data also suggest that there may be a pharmacodynamic interaction between SSRIs and oral anticoagulants that can cause an increased bleeding diathesis. Concomitant administration of paroxetine and warfarin, specifically, has been associated with an increased frequency of bleeding without apparent changes in the disposition of either drug or changes in the prothrombin time. Bleeding has also been reported with fluoxetine and warfarin, while citalopram and sertraline have been reported to prolong the prothrombin time of patients taking warfarin by about 5% to 8%. In the RE-LY study (Randomized Evaluation of Long-term anticoagulant therapy), SRIs were associated with an increased risk of bleeding in all treatment groups.

MANAGEMENT: Caution is advised if SRIs or clomipramine are used in combination with other drugs that affect hemostasis. Close clinical and laboratory observation for hematologic complications is recommended. Patients should be advised to promptly report any signs of bleeding to their physician, including pain, swelling, headache, dizziness, weakness, prolonged bleeding from cuts, increased menstrual flow, vaginal bleeding, nosebleeds, bleeding of gums from brushing, unusual bleeding or bruising, red or brown urine, or red or black stools.

Given that your husband has severe anxiety, the use of interferons may be contraindicated. Since he is HU-intolerant, Jakafi is a logical next choice. While there are potential drug interactions, these need to weighed against the risk of inadequately treated PV. It sounds like his hematologist has weighed the risks and made a recommendation based on your husband's risk profile.

Suggest reviewing your concerns with the hematologist to get the best case-specific answer to your questions. It may also be a good idea to get a second opinion from a MPN Specialist. Just in case you need it, here is a list. mpnforum.com/tsr-the-list/

Wishing you and your husband all the best.

[DaisyJayne1 in reply to hunter5582]

Thank you Hunter! We do always check with his team of doctors, as well as the pharmacist. There is always room for human error and we want to make the most informed choice possible.

[Anag]

hi daisy, I don’t know much about the enzymes but I do you know about anxiety and depression. I suffered from depression on and off all of my life until I finally cleaned up my diet and went organic and also reduced actually eliminated, all greens, except rice, all milk products and other Foods that I was intolerant to. I also did a lot of good repair like 24 hour cooked bone broth, L glutamine and Build up my digestive bacteria, which had been ravaged by all the antibiotics I had previously taken in my life.

I also got rid of every single chemical that comes into my house or onto my skin. I stopped all sugars and processed foods!!! I cannot stress enough, how important all that is, because our liver, kidneys and detox pathways are extremely overloaded in our world today. Once we give them a break from all the other unnecessary chemicals, heavy metals, et cetera coming in, then our metabolism and other important functions are able to work better.

all this is, especially important to us who taken such strong medications over a long period of time. We basically have to reduce our toxic load as much as possible. It is a long process, but it is doable.

My fatty liver, depressions, bloating, body oder, histamine intolerance, dental plaque, 25kg extra, brain fog, sleep problems, anger issues, debilitating fatigue, chronic sinus infections and colds, etc are now all a thing of the past for 6 years!!

Hope this helps a bit. My diet is autoimmune paleo.

[DaisyJayne1 in reply to Anag]

Thank you! Agree with diet and gut microbiome clean up 💯.

[Leveret20]

I am not on Jakafi, but I have always battled anxiety, worse in the last ten years. Various GPs have prescribed various anti-depressants over the years and none of them helped much.

At the time of diagnosis the Macmillan service in the hospital referred me for counselling. It was EMDR - Eye Movement Desensitisation and Reprocessing - it has been the only thing that ever really helped my anxiety and it transformed my life.

Caveat - we are all different , and you have to have a therapist you can trust, but if you have an opportunity, it is worth a try.