Antipsychotic & antidepressant withdrawal & histamine

[lucyinthesky]

Hi guys, I’ve been doing some research into histamine since I believe it plays a very key role in the withdrawal process--at least from the medications that I’m on. I will summarise what I’ve found below as well as the potential impact it could have on managing the withdrawal from antipsychotics such as Zyprexa/Seroquel. I searched this forum but couldn’t find any good overview or discussion, so hoping this can help people.

 

• Many of the popular antipsychotics such as Olanzapine/Zyprexa and Seroquel/Quetiapine have a very powerful antihistamine effect: only a very small amount of these medications are required to block the H1 Histamine receptor. Zyprexa, for example, has a Ki(nM) of 0.65–4.9 according to Wikipedia, which is incredibly low (the lower the Ki(nM), the smaller the amount of a medication is needed to block a certain receptor).
   
• Therefore, withdrawing from histamine-blocking medications (Zyprexa/Seroquel) is associated with increased histamine (as the blocking effect is reduced, histamine levels become elevated).
   
• Certain groups of people might have even had a histamine intolerance and/or high histamine before going on psych-drugs (and both histamine intolerance and high histamine--also related to under-methylation--have been linked to psychosis and other psychiatric disorders), so coming off histamine-blocking medications can also exacerbate this pre-existing imbalance, on top of the effect described in the point above.
   
• Histamine is a neuromodulator of the adrenals, so elevated histamine can make the adrenals release a lot more adrenaline, instigate ‘fight or flight’ mode in the body and cause severe anxiety. There is also a strong link between histamine and sleep; having high histamine can cause insomnia. Interestingly, histamine levels naturally peak around 3am/4am, which is when many people experience cortisol spikes and unwanted adrenal activity. Sound familiar? All of these symptoms are very common in the withdrawal process, as we unfortunately know.
   
• When withdrawing from histamine-blocking medications, you can take steps to bring down histamine levels to help manage the adverse effects mentioned above. I’ve found anecdotal success stories online from the world of integrative medicine; Alice Lee (MD) says: “If you ever want to successfully reduce a medication that blocks histamine receptors, you will need to know how to lower histamine levels.”
   
• Lowering histamine levels can be done through a combination of diet and supplementation:
  • 1) Follow a low-histamine diet (google it for more info!)
  • 2) Through supplementation - taking a histamine digester that ‘chews up the histamine in food’ - Alice Lee recommends Histazyme (by Dr. Amy Myers, MD), but I’ve also seen Daosin 50 and other brands which all contain the same ingredient, Daimine Oxidase
    3) Supplementation - natural histamine blockers like Allqlear by Integrative Therapeutics, Histaplex A-B by Biotics Research, or Opsin II by DesBio.  
    • Avoid xenobiotics for antihistamine support, such as Benadryl, because the body will react with an inflammatory response to a xenobiotic.
       
• I know that this kind of integrative approach is generally a dirty word on this forum, but for me it makes too much sense to ignore. Most of this advice comes from Alice Lee, who is a “holistic psychiatrist” who actually went through the withdrawal process herself, and reports impressive success stories weaning her clients off all kinds of medication (APs, ADs), just check the testimonials on her website
   
• TL;DR: I’m going to try a low histamine diet (being more careful around the time when I make a cut to my medication), as well as adding some of the anti-histamine supplements and histamine digesters. I will still be tapering using the 10% method.

 

If anyone else has research or real experience in this area, I would be very curious to hear it. I think it is a very under-recognised factor and understanding more could potentially make for a smoother withdrawal. I'm also conscious that it's only one piece in the puzzle, and there are other receptors to tackle too. But for insomniac, Zyprexa-dependent folks like myself, it could be really key.

More reading and links to the success stories can be found here:

 

http://www.holisticpsychiatrist.com/viewpoint/2018/6/7/understanding-histamines-connection-to-mental-health

and http://www.holisticpsychiatrist.com/medication-withdrawal/

 

https://beyondmeds.com/2014/07/13/histamine-psych-drugs/ and https://beyondmeds.com/2013/01/07/histamine-intolerance/

 

 from around 33 mins

 

https://www.mthfrsupport.com.au/dao-deficiency-and-histamine-the-unlikely-connection/

[Lloyd]

Interesting... I suspected histamine may play some role in SSRI withdrawl. AM going to talk to my doc this week about it./

Also found an article here too which explains in detail.

 

http://alisonvickery.com.au/the-anti-depressant-brain-fog-and-histamine-intolerance-connection/

 

[Altostrata]

I don't believe anti-histaminic activity has any bearing on withdrawal. This used to be called anti-cholinergic and applied to tricyclic antidepressants (TCAs). It was thought withdrawal syndrome was due to "cholinergic rebound" and since "selective serotonin reuptake inhibitors" (SSRIs) were not anti-cholinergic (except for paroxetine, as it turned out), they would incur no withdrawal syndrome.

 

This assumption was proved wrong as SSRIs have a withdrawal syndrome just like the TCAs and very much like benzodiazepines -- all very different drugs. Withdrawal syndrome is dependent on widespread dysregulation of neurohormonal systems, not just activity at the serotonin or histamine receptors.

 

(Activity at histamine or cholinergic receptors tends to make people sleepy or groggy.)

 

The histamine or cholinergic systems are simply other neurohormonal systems that can get dysregulated by psychiatric drugs. It's a myth that only specific systems are affected.

[Iatrogenesis]

Hi, I just wanted to say I'm a Zyprexa survivor, and while I have never tried the anti-histamine diet (or the other things you mention), as you said a lot of APs have a very high histamine receptor binding affinity (so low K_i (nM) ) and that would be because they were, I believe, actually derived from the Anti-Histamines, which are sold as allergy and insomnia drugs. Now, I'm an allergy sufferer and during my childhood I did a lot of anti-histamines, and that's how, I believe, I was made to be dependent on APs.

[Altostrata]

Prim Care Companion J Clin Psychiatry. 2004;6(Suppl 2):3-7.

Atypical antipsychotics: sleep, sedation, and efficacy.

Miller DD1.

 

Abstract at https://www.ncbi.nlm.nih.gov/pubmed/16001094 Full text https://www.ncbi.nlm.nih.gov/pmc/articles/PMC487011/

 

Patients with schizophrenia often suffer from sleep disturbances such as excessive sleeping and insomnia. Common medications for schizophrenia can have a sedative effect on patients. Not all antipsychotic medications have the same sedative effect, which is related to dosage and affinity for histamine H1 receptors. Studies have shown that, compared with conventional antipsychotics, atypical antipsychotics such as risperidone, olanzapine, quetiapine, and ziprasidone generally cause less sedation yet are as effective in controlling psychosis and agitation. Sedation can be troublesome to patients who are trying to become re-integrated into society and interfere with their treatment regimen. Both persistent sedation and chronic insomnia can be managed by the physician.

 

From the paper:
 

Quote

....

Studies have indicated that sedation may also be related to the affinity of the medication for the histamine H1 receptors. The antipsychotics vary in their ability to block these receptors.4,7 A study by Richelson and Souder7 of the binding profiles of antipsychotic medications found that olanzapine has the highest affinity for the histamine H1 receptors, followed by clozapine (Figure 1). This may explain why olanzapine has a relatively large sedative effect even though it is a high-potency medication. Of the antipsychotics studied, haloperidol had the lowest affinity for the histamine H1 receptors. Quetiapine and risperidone had the lowest affinity of the atypical antipsychotics.

....

Although both dosage and affinity for histamine H₁ receptors play a part in the sedative effect of a medication, what ultimately determines sedative effect is the amount of the drug reaching the histamine H₁ receptors in the central nervous system. For example, quetiapine, which has little affinity for the histamine H₁ receptors, is a less potent antipsychotic medication and requires many more milligrams to be effective than do higher-potency medications such as risperidone and ziprasidone. Because of this, quetiapine has a greater sedative effect on patients in clinical use than do risperidone and ziprasidone.

 

When analyzing the relative effects of several medications, it is useful to choose studies that used a second medication and a placebo as controls. For example, the sedative properties of risperidone and other atypical antipsychotics can be seen by comparing their effects with those of haloperidol in clinical trials (Figure 2).

....

Sedation used to be considered necessary for the efficacy of antipsychotic medications in controlling the positive symptoms of schizophrenia, such as psychosis, but, with the atypical agents, psychosis and acute agitation can be controlled without sedation. A review by Marder et al.¹² of 2 North American trials of risperidone found that it was as effective as haloperidol at reducing the positive symptoms of schizophrenia. Two-mg/day and 6- to 16-mg/day doses of risperidone were compared with a 20-mg/day dose of haloperidol. The 2-mg/day dose of risperidone had approximately the same effect on positive symptoms of schizophrenia as the 20-mg/day dose of haloperidol (Figure 3). The severity of positive symptoms improved similarly in the 2-mg/day risperidone-treated group and the haloperidol-treated group, according to the changes in scores on the positive symptoms factor of the Positive and Negative Syndrome Scale (PANSS). Neither haloperidol nor risperidone has a high affinity for H₁ receptors, but risperidone is effective at lower doses, which may make a difference in its sedative effect on patients.

....

CONCLUSION

Sleep disturbances and sedation are common in patients with schizophrenia. There are differences in the actual sleep process between patients with schizophrenia and individuals with no psychiatric disorders. Many antipsychotic medications cause sedation, but not all medications have the same sedative effect. Sedation is related to the amount of medication reaching the central nervous system, which is determined by dosage and the drug's affinity for histamine H1 receptors. Atypical antipsychotics often cause less sedation than do conventional antipsychotics while providing similar or greater reduction in symptoms. Sedation can cause problems for patients and is often unnecessary, as both psychosis and agitation can be managed without sedation. If persistent sedation is a problem, there are steps that physicians can take to minimize the sedative effect of antipsychotic medication. Chronic insomnia can also be treated by the physician.

....

 

 

[papaloapan]

On 3/4/2019 at 2:42 PM, Altostrata said:

For example, quetiapine, which has little affinity for the histamine H₁ receptors, is a less potent antipsychotic medication and requires many more milligrams to be effective than do higher-potency medications such as risperidone and ziprasidone.

A neuropsychiatrist told me that 100mg of quetiapine "is not a therapeutic dosage" of quetiapine for my "bipolar affective disorder", that I should take 300mg of quetiapine because 300mg "is a therapeutic dosage". When I took 300mg I fell asleep the entire day. And with 100mg I'm drowsy since I wake up from bed till 2pm, along with other adverse effects.

[Altostrata]

On Facebook, people going off mirtazapine, which is anti-cholinergic, seem to be reported an unusual frequency of histamine intolerance (a food intolerance), which might be an aspect of cholinergic or histaminic rebound in mirtazpine withdrawal syndrome.

 

It is possible that the action of antipsychotics becomes more anti-cholinergic at lower doses, producing sleepiness and fogginess, but it's unclear where the dividing line may be. 

 

See 

 

[tsranga]

20 hours ago, Altostrata said:

On Facebook, people going off mirtazapine, which is anti-cholinergic, seem to be reported an unusual frequency of histamine intolerance (a food intolerance), which might be an aspect of cholinergic or histaminic rebound in mirtazpine withdrawal syndrome.

 

It is possible that the action of antipsychotics becomes more anti-cholinergic at lower doses, producing sleepiness and fogginess, but it's unclear where the dividing line may be. 

 

See 

 

 

Yup.. Mirtazapine withdrawal has really affected my histamine and adrenal processing and I can relate to what the OP summarizes even 3 years post CT withdrawal.

 

Interestingly enough, acupuncture has really helped tame the fight/flight response and temperature sensitivity, so the histamine flare-ups (mainly due to weather changes) have been more manageable.

 

[Mirtazapain]

On 6/21/2018 at 9:44 AM, lucyinthesky said:

Therefore, withdrawing from histamine-blocking medications (Zyprexa/Seroquel) is associated with increased histamine (as the blocking effect is reduced, histamine levels become elevated).

 

Thank you, thank you for this post. It really resonates with me. I am not tapering off Seroquel, but am having similar difficulties with mirtazapine. 

 

Like Seroquel, mirtazapine is essentially 2 different drugs at high vs low doses. Seroquel is an antipsychotic at high doses and sedating at low doses. Mirtaz is activating at high doses (< 30 mg) because it is an alpha 2 agonist (blocks norepinephrine and some serotonin). But at low doses (7.5 mg and lower) it bonds almost exclusively to the H1 (histamine) receptor. Making it one of the strongest antihistamines in the world. This is why it is so sedating and causes weight gain. 

 

It also bonds to HT2 (blocking serotonin), but much less exclusively, particularly below 7.5 mg.

 

(Read The Last Psychiatrist's papers on the mode of action of Seroquel and on why mirtazapine is so sedating in his blog post about sleep. He explains things much better than me!)

 

Some reports suggest that mirtazapine has upwards of 95% occupancy of the H1 receptor at 7.5 mg. This means that from 7.5 mg down, to taper is to fall off a cliff, and to greatly expose oneself to histamine that had formerly been blocked by the antihistamine affect of mirtazapine. 

 

This reflects my experience tapering off mirtazapine. From 22.5 to 7.5 mg (at 10% / month) my wd symptoms were relatively minor and of the agitation, irritability, and anxiety variety. Because receptor binding is linear up in this dose range, I was losing approx. 1% receptor occupancy with each drop. 

 

From 7.5 mg to 6.75 mg everything changed. This is where occupancy becomes exponential.  I calculate that I lost, at minimum, 7.5% H1 occupancy in my first 10% drop. That's 7.5x more than any of my previous drops. That's a lot of excess histamine to process. 

 

The first 14 days followed my 'normal' pattern: agitation, anxiety, and irritability. But worse. Then, on day 21 a new set of symptoms arrived: shaking, nausea, adrenaline surges, headache, diarrhea, and sweating. These are histamine-mediated and so I wonder if I am now basically swimming in histamine along with adjusting to lower serotonin? 

 

The sad truth is that no one knows. At least in the scientific literature. No one really know what mirtazapine does. And no one really knows what to do about all this excess histamine. My doctor literally snorted when I suggested this. 

 

We are all in this together. Trying to make sense of what is happening to our bodies and our minds. The fact is, mirtazapine is very different from the other SSRIs in terms of its mode of action and receptor binding affinities and perhaps excess histamine is one of issues when tapering off. 

 

I am going to explore the low histamine diet and other supplements that digest histamine. That and significantly slow down my taper! 

 

So, thank you lucyinthesky! 

[FeralCatman]

After tapering Seroquel over 3 years and 4 months, ending August 1 2021, I seem to have developed a really nasty histamine intolerance or sensitivity. Right now I have to wear an N95 any time I leave the house because allergy season is tipping me over the edge which I have never had to do. Currently I am having to take Allegra twice daily to keep things at bay. I have drifted into stage 2 anaphylaxis 3 times now and had to use benadryl and oxygen as rescue medications. I am working with an immunologist for some testing for MCAS and a few other things and am going to see a functional nutritionist who specializes in dealing with these sorts of things. I am also using acupuncture. It's been crazy and a bit scary as none of my doctors really know what to do so I am largely dealing with this on my own and with input from this website. It feels a bit like flying a plane in the clouds with nothing but an altimeter. All I can do is try to fly high enough to not hit a mountain until I come out of the clouds and can see around me again. My immunologist is not back in the office until May and my next appointment is not until June 7. I have already started a low histamine diet but it has not been enough to calm things in combination with allergy season hence the Allegra twice a day. So, whether this is withdrawal related, an exacerbated pre-existing condition, gut damage, etc. who really knows. I do know that prior to coming down off of the Seroquel all I had was some springtime anxiety and typical seasonal allergy symptoms during tree pollen season. Over the last few weeks I have had reactions to things I have never had an issue with. So, whatever the cause, Histamine can definitely wreak havoc with your life.