Abilify tolerance

[leokitten]

On our List is also passion flower, 5-HTP, hop, L-tryptophan, glycin, GABA, theanine, taurine and i also read that some antidepressants could work at a low dose, but again not so sure about these things in combination with the drug holidays. Would be very happy about any ideas & tips.

I find that the sleep problems in ME are so bad that natural stuff just isn’t even close to strong enough, it’s sad to say but I consider myself a prime example of a pwME with sleep issues as one of my major symptoms.

Only pharmaceutical grade sleep meds really work for me, and it’s not due to tolerance or anything like that, its been that way since the beginning of the ME sleep issues about 9 months into the illness in 2013. I tried all those natural supplements you’ve listed, they simply do not work unless my sleep issues are in a minimal fluctuation.

I personally don’t believe sleep meds are going to affect his tolerance to Abilify over these months, no need to completely torture yourself by making this absolute drug holiday

We cannot give medical advice, but drugs that have worked for me are:

tiagabine 4-8 mg
clonidine 0.1 mg
hydroxyzine 25-50 mg

These will generally put anyone down to bed, especially in combination. They also take a long while before you build up tolerance.

And when sleep disturbances are so horrible that I am in tears not sleeping for days and nothing works, then

eszopiclone 3 mg
lorazepam 2 mg

Either of these works well in an emergency. I know I’ve warned a lot against benzos or z-drugs in other posts, but in an occasional emergency I do believe it’s ok since nothing else will work and I’m awake in excruciating ME pain for days.

 

[Push Fwd]

@Push Fwd Has Martin gotten worse than he was pre abilify?

It‘s hard to tell cause there were a lot of factors in the last weeks that effected his health in a bad way (e.g. he had to get a tube again, the tube was infected - so he had to be 2 times in hospital, had to take antibiotics etc.).

I find that the sleep problems in ME are so bad that natural stuff just isn’t strong even close to enough, it’s sad to say but I consider myself a prime example of a pwME with sleep issues as one of my major symptoms.

Only pharmaceutical grade sleep meds really work for me, and it’s not due to tolerance or anything like that, its been that way since the beginning of the ME sleep issues about 9 months into the illness in 2013.
[...]

Thank you very much, but the problem is not so much to fall aspleep, it‘s more about sleeping long enough. Most of the time he sleeps early but just a few hours and then he can‘t find sleep again. So we are looking for something that could help longterm. Thats why real sleep meds are not an option.

 

[leokitten]

Thank you very much, but the problem is not so much to fall aspleep, it‘s more about sleeping long enough. Most of the time he sleeps early but just a few hours and then he can‘t find sleep again. So we are looking for something that could help longterm. Thats why real sleep meds are not an option.

Same for me @Push Fwd, I meant every aspect of sleep is affected by my ME. Getting tired, falling asleep, sleep disturbances in the middle of the night, being jolted awake by more sleep disturbances too early, not sleeping long enough, having really poor quality sleep, I could go on.

I found the only long-term solution is pharmaceutical grade sleep meds and cycling through different ones and combos. It’s the only way to minimize tolerance. I’ve been doing for 7.5 years and it still works ok.

I wish I could tell you natural solutions would work as well but unfortunately they don’t even come close and there’s no difference you will build up tolerance from natural supplements just as fast as pharmaceuticals, there’s no free lunch. Natural solutions/supplements are just as problematic long-term if they ever even work well enough.

 

[WantedAlive]

I have a couple of questions for those who have been using Abilify. @leokitten @Martin aka paused||M.E.

I ask those who have discontinued or paused, have you had to titrate down or can you discontinue cold turkey without problems? I assume dose must come into play here, so is there a dose level up to the recommended maximum 2mg that one should step-down before discontinuing?

The other question I ask relates to a possible theory why Abilify might be working. Have you noticed any change to peripheral circulation, body temperature and cold extremities?

Why I ask this relates to low-dose dopamine being used for ‘cold shock’ resuscitation. PwME present with most of the symptoms representing (septic) cold shock: decreased stroke volume, preload failure, impaired contractility, narrowed pulse, normal or increased diastolic, delayed capillary refill, cold extremities, pale dry skin, peripheral vasoconstriction, shallow respirations, etc. It’s almost as if PwME are trapped in a chronic cold-shock syndrome, and with it the weakness and stress vulnerability that accompanies shock.

Refer Medscape Septic Shock Treatment & Management:

Dopamine should be used only in certain highly specific situations, such as when there is a low risk of tachyarrhythmias and in the presence of coexistent bradycardia.

Dopamine may be particularly useful in the setting of cold shock, where peripheral vasoconstriction exists (cold extremities) and cardiac output is too low to maintain tissue perfusion.

Dosages range from 2 to 20 µg/kg/min. A dosage lower than 5 µg/kg/min results in vasodilation of renal, mesenteric, and coronary beds. [11] At a dosage of 5-10 µg/kg/min, beta1 -adrenergic effects induce an increase in cardiac contractility and heart rate. At dosages of about 10 µg/kg/min, alpha-adrenergic effects lead to arterial vasoconstriction and elevation in blood pressure. [11].

I’m wondering therefore, if a critically controlled dopamine level is addressing the cardiac output and peripheral vasoconstriction. With the long half-life of Abilify, the discussed dose threshold at which the increased dopamine level becomes detrimental is very plausible.

Why might dopamine be low? High Angiotensin II levels in ME/CFS could be to blame. Recall the connection between Covid19 and ME/CFS which could be centered around bradycardia and the renin-angiotensin-aldosterone (RAS) system, which was well described in HR here. Well, dopamine seems to be involved in the cross talk between RAS and inflammation, which is well described and an interesting read in these two papers, there may be some discussion points in here:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526080/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4086395/

 

[leokitten]

I ask those who have discontinued or paused, have you had to titrate down or can you discontinue cold turkey without problems? I assume dose must come into play here, so is there a dose level up to the recommended maximum 2mg that one should step-down before discontinuing?

There’s no correlation I’ve seen among people trialing Abilify if they get withdrawal or not and the dosage before discontinuation

The other question I ask relates to a possible theory why Abilify might be working. Have you noticed any change to peripheral circulation, body temperature and cold extremities?

No I haven’t noticed

Why might dopamine be low?

My theory is that the dopamine network and basal ganglia require a lot of energy to function properly, more energy than any other part of the brain. I believe the caudate-putamen is the highest energy consuming area of the brain on a volumetric basis in fact.

So the dopamine network is much more sensitive to peripheral immune activation causing neuroinflammation, reductions in cerebral blood flow and oxygen delivery, microcirculation, mitochondrial impediments, etc.

 

[Judee]

I did ask this but maybe on another thread. Is dosing daily and if so, has anyone's doctor recommended taking the medication every other day or every third day?

I remember Janet Defoe saying that Whitney could only take Ativan (I know, different drug) once in a while or it stopped working.

Just wondered if anyone had tried spacing the dosing and found the medication kept working for them longer than just 4-6 months.

 

[mitoMAN]

Ativan is a benzo and will create quick tolerance buildup especially if taken in high dosages.
Thats not the case with most anti-depressants and probably not with Abilify. We are taking VERY low dosages that wont oversaturate receptors.

 

[leokitten]

I did ask this but maybe on another thread. Is dosing daily and if so, has anyone's doctor recommended taking the medication every other day or every third day?

I remember Janet Defoe saying that Whitney could only take Ativan (I know, different drug) once in a while or it stopped working.

Just wondered if anyone had tried spacing the dosing and found the medication kept working for them longer than just 4-6 months.

Not dosing daily with Abilify doesn't really serve any purpose. It has a very long half-life so at steady state taking e.g. 0.25 mg every 2 days will just turn out to have the same steady state concentration let's say to 0.1 mg every day (it's likely not accurate but you get the point). It just will translate to the same steady state concentration as taking some lower amount daily.

 

[leokitten]

@Hip and others, regarding tolerance, and if the dopamine autoreceptor downregulation hypothesis is the reason why after ~3-4 months Abilify stops working in ME, would taking SSRI/SNRI/MAOI antidepressants have a positive effect? I read here that antidepressants reduce the sensitivity of dopamine autoreceptors, see section "EFFECT OF ANTIDEPRESSANT ON DOPAMINERGIC ACTIVITY":

Antidepressant-induced Dopamine Receptor Dysregulation: A Valid Animal Model of Manic-Depressive Illness. Demontis et al. Curr Neuropharmacol (2017)

 

[Hip]

@Hip and others, regarding tolerance, and if the dopamine autoreceptor downregulation hypothesis is the reason why after ~3-4 months Abilify stops working in ME, would taking SSRI/SNRI/MAOI antidepressants have a positive effect?

Hard to say, I haven't yet got my head around the full complexities of Abilify's effects at the dopamine receptor and dopamine autoreceptor. I would like to get a feel for the dynamics of this.

It's complex stuff, and at my present levels of brain fog, I find it hard going. But next time I get a clear head, I will try to get to grips with it.

If you Google search for aripiprazole dopamine presynaptic autoreceptor, there are several studies which give some detail.



From what little I know, I would not have thought low-dose Abilify would down-regulate the dopamine autoreceptor, as this drug blocks the autoreceptor, so if anything you might expect autoreceptor up-regulation.

If there is autoreceptor up-regulation, then that might explain the Abilify loss of effect experienced by some ME/CFS patients, as an increased autoreceptor signal will induce more DAT (dopamine transporter) in the synapse, which will lower dopamine levels.

 

[leokitten]

From what little I know, I would not have thought low-dose Abilify would down-regulate the dopamine autoreceptor, as this drug blocks the autoreceptor, so if anything you might expect autoreceptor up-regulation.

If there is autoreceptor up-regulation, then that might explain the Abilify loss of effect experienced by some ME/CFS patients, as an increased autoreceptor signal will induce more DAT (dopamine transporter) in the synapse, which will lower dopamine levels.

Sorry this is my brain fog now! This is what I actually meant, that by antagonizing the dopamine presynaptic (auto)receptor, evenutally that would result in increased expression of the receptor, and more receptors being present at the presynaptic membrane and that would negatively influence Abilify's stimulation of dopamine activity.

 

[Hip]

Just doing a bit of Googling about dopamine autoreceptors, and found a couple of studies which suggest possible methods of down-regulating the dopamine autoreceptor, to try to combat the Abilify loss of effect:

This study found that 5 days of amphetamine reduces dopamine D2 autoreceptor function.

So getting hold of some Adderall (not an easy task) and taking it for a few days might possibly remedy the Abilify loss of effect. There are no drug interactions between these two drugs, according to drugs.com.


This study found that the tricyclic antidepressants amitriptyline and imipramine reduce the sensitivity of dopamine D2 autoreceptors.

So possibly co-administration of amitriptyline or imipramine with Abilify may remedy or prevent the loss of effect. There is a moderate drug interaction between Abilify and amitriptyline, so some caution would be advised. Though with the low-dose Abilify protocol, these interactions will be much less.

 

[leokitten]

This study found that the tricyclic antidepressants amitriptyline and imipramine reduce the sensitivity of dopamine D2 autoreceptors.

So possibly co-administration of amitriptyline or imipramine with Abilify may remedy or prevent the loss of effect. There is a moderate drug interaction between Abilify and amitriptyline, so some caution would be advised. Though with the low-dose Abilify protocol, these interactions will be much less.

Yes I believe this study and another similar one were referenced in the study I linked. Seems like multiple antidepressants actually reduce the sensitivity of dopamine autoreceptors, so might not only be TCAs but pretty much everything that increases serotonin activity?

But the side effect from many antidepressants is that they also lower dopamine activity (so cutting into Abilify’s efficacy if indeed it’s all about increased dopamine activity), so I would guess antidepressant dosage must be fine tuned to get best of both worlds, reduce tolerance and not reduce increased dopamine activity too much.

 

[leokitten]

But the side effect from many antidepressants is that they also lower dopamine activity (so cutting into Abilify’s efficacy if indeed it’s all about increased dopamine activity), so I would guess antidepressant dosage must be fine tuned to get best of both worlds, reduce tolerance and not reduce increased dopamine activity too much.

One reason too that I’ve been combining the RIMA MAOI moclobemide along with aripiprazole, as it works differently than SSRI/SNRIs and mechanism of action should hopefully counteract lowering of dopamine activity due to increased serotonin activity because inhibits breakdown of dopamine.

 

[pattismith]

It‘s hard to tell cause there were a lot of factors in the last weeks that effected his health in a bad way (e.g. he had to get a tube again, the tube was infected - so he had to be 2 times in hospital, had to take antibiotics etc.).

I'm sorry to read Martin is struggling so much at the moment. Some PR members take anti-histamine drugs for sleep, did Martin tried it?

 

[pattismith]

I wonder if Perospirone (blocker of D2 dopamine receptors) has similar effect on Dopamine balance as Aripiprazole?

Perospirone, a novel atypical antipsychotic drug, potentiates fluoxetine-induced increases in dopamine levels via multireceptor actions in the rat medial prefrontal cortex - PubMed (nih.gov)

 

[leokitten]

I'm sorry to read Martin is struggling so much at the moment. Some PR members take anti-histamine drugs for sleep, did Martin tried it?

I recommended one (hydroxyzine) in my list of personally effective sleep meds in my post to @Push Fwd. Hydroxyzine also doesn’t seem to have anticholinergic properties like many other antihistamines do.

But like all H1 antihistamines, it can cause weight gain, and like all effective sleep meds and natural supplements, you eventually cannot sleep without them. But with ME severe sleep problems you have to make hard choices because not sleeping or having sleep disturbances makes my ME worse, so would rather be habitually dependent on sleep meds and have more control ME symptoms than be in insomnia and sleep disturbance hell on top of worse ME.

 

[leokitten]

I wonder if Perospirone (blocker of D2 dopamine receptors) has similar effect on Dopamine balance as Aripiprazole?

Perospirone, a novel atypical antipsychotic drug, potentiates fluoxetine-induced increases in dopamine levels via multireceptor actions in the rat medial prefrontal cortex - PubMed (nih.gov)

There was another dopamine autoreceptor agonist Merck discovered and researched called roxindole

 

[YippeeKi YOW !!]

@pattismith , @Martin aka paused||M.E. ,

I'm sorry to read Martin is struggling so much at the moment. Some PR members take anti-histamine drugs for sleep, did Martin tried it?

I',m so glad you mentioned that ..... I was going to post something in that area that works like a charm for me when I'm desperate to get some shut-eye, but was hesitant because I was afraid that it was off-topic, and I'm uncertain how that would interact with the traces of Abilify that might still be in Martin's system ....

I found Benadryl to have a paradoxical and very unpleasant effect, but Unisom, which is doxylamine succinate, is absolutely perfect. I take about 1/4 to 1/3 of a 25 mg tab, and within 45-60 mins max I'm struggling to stay awake.

When I'm lucky, it keeps me asleep for much of the night, and I have no hangover effect from it, beyond a little fuzziness that a cup of weak coffee can send packing ....

 

[YippeeKi YOW !!]

Hydroxyzine also doesn’t seem to have anticholinergic properties like many other antihistamines do.

I believe that it does have anticholinergic properties, tho I'm not dead certain. It's also available by prescription only, which makes it less easily available without a Drs appt and the attendant costs of that, and is used off-label to treat anxiety along with 'nervousness' .....

Did a quick google just to be sure about what I thought I remembered about Atarax (hydroxyzine), and it is anticholinergic:

"Atarax (hydroxyzine hydrochloride) is an antihistamine with anticholinergic (drying) and
sedative properties used for symptomatic relief of anxiety and tension
associated with psychoneurosis and as an adjunct in organic
disease states in which anxiety is manifested."
https://www.rxlist.com/atarax-side-effects-drug-center.htm#overview
​

It also has a longish list of unpleasant side effects that might or might not manifest. I've found nothing similar with Unisom, for what it's worth .....

​