Aripiprazole - Abilify

[chelby]

One of the main issues currently that’s been talked about on PR is about how long the improvements on Abilify last. Some people have reported that after a couple months or more their improvements reduced...

I wonder if it is because it has built up in their system and so is no longer a microdose? AKA could it start having an agonistic effect on dopamine like it is intended to do at therapeutic doses for psychiatric illness?

(I am not 100% clear if it is antagonistic or agonistic at microdoses, need someone to confirm. I know people have said it in this thread but I am not fully understanding)

 

[leokitten]

I wonder if it is because it has built up in their system and so is no longer a microdose? AKA could it start having an agonistic effect on dopamine like it is intended to do at therapeutic doses for psychiatric illness?

(I am not 100% clear if it is antagonistic or agonistic at microdoses, need someone to confirm. I know people have said it in this thread but I am not fully understanding)

Medications don’t build up in your body under normal conditions, your body works naturally to metabolize and excrete them. It would be very dangerous to your body if drugs could do that normally.

Regardless of the half-life of a drug, when a person takes the same dosage of a medication on a consistent basis, eventually the concentration of the drug in the body reaches a steady state and stays there (usually after a couple weeks). The half-life of a drug guides how often you have to dose.

At antipsychotic doses, Abilify is antagonistic at all dopamine receptor types and two serotonin receptor types, though at very low doses used in ME, it acts as an agonist at these same receptors, so effectively acts like a somewhat different drug.

Not sure why it eventually stops working in some people after a couple months after such significant and fast improvements once they started taking it. For sure one possible reason is that it’s likely a symptomatic treatment not disease modifying. Plus this fading seems to happen with almost every drug in ME.

 

[Wits_End]

It seems almost to good to be true. My main concern is - does Abilify improve the underlying disease or does it make you feel good (a false sense of wellbeing?)

This is precisely what I've been asking, as I've mentioned previously. If it is giving you a false sense of wellbeing, then what is the additional exertion doing to your underlying condition? So I'd be interested in hearing what happens if people come off it.

Also to be borne in mind is that aripiprazole lasts for over 3 days in the body, so you will get a build-up.

 

[leokitten]

You will not get a consistent build up over time even for drugs that have a much longer half-life than the dosing frequency. It will still reach a steady state. Again I’m not making this up it’s standard pharmacokinetics.

 

[leokitten]

This is precisely what I've been asking, as I've mentioned previously. If it is giving you a false sense of wellbeing, then what is the additional exertion doing to your underlying condition? So I'd be interested in hearing what happens if people come off it.

The few reports I read from people where it stopped working is they were no worse off than baseline before Abilify.

 

[leokitten]

My main concern is - does Abilify improve the underlying disease or does it make you feel good (a false sense of wellbeing?)

Disease modifying is where the drug targets a specific part of the underlying disease pathology. Take for example in psoriasis it’s known CD23+ overactive B cells are a core part of the disease pathology and inflammatory milieu. Modern biologics (monoclonal antibodies) target CD23, signaling to the immune system to kill these overactive cells, therefore modifying the disease and alleviating symptoms.

Symptomatic treatment is also not necessarily “feeling good”, it could be e.g. ME causes neuroinflammation in the basal ganglia or other areas due to some underlying root ME pathology (even outside the brain), and neuroinflammation is known to cause neurotransmitter dysfunction and receptor downregulation, and dysfunctional neurotransmission of dopamine and serotonin causes certain symptoms. So Abilify helps to correct some of this neurotransmission and alleviates some symptoms.

 

[leokitten]

https://www.medscape.com/viewarticle/448250_3

Half-life and Steady State
One of the main reasons for this gets back to the issues of pharmacokinetics. To review some of the basics of pharmacology, medications vary in how long it takes to clear them from the body. Some are metabolized fairly quickly, while others can take a long time before they are eliminated. We quantify this with the use of the term "half-life." The half-life of a given medication is how long it takes for the body to get rid of half of the dose. When the patient is taking a medication on a regular basis, there is an ongoing process of drug absorption in the form of each dose of the drug and, concurrently, an ongoing process of drug removal with the drug's metabolism and clearance. Eventually, there comes a point when the amount of drug going in is the same as the amount of drug getting taken out. We call this "steady state." It takes somewhere between 5 and 6 half-lives for a medication to reach steady state. Thus, medications with short half-lives reach steady state relatively quickly, while those with long half-lives take a long time to reach steady state.

 

[Milo]

Medications don’t build up in your body under normal conditions, your body works naturally to metabolize and excrete them. It would be very dangerous to your body if drugs could do that normally.

Regardless of the half-life of a drug, when a person takes the same dosage of a medication on a consistent basis, eventually the concentration of the drug in the body reaches a steady state and stays there (usually after a couple weeks). The half-life of a drug guides how often you have to dose.

Hi @leokitten I tend to agree with you to a degree, and you made sure to mention ‘under normal conditions’. However there are certain drugs that require careful monitoring such as lithium, tobramycin, gentamycin and others. Drugs that depend on a normal kidney and liver function will become toxic if these change, and it certainly can change. Valtrex and Valcyte are 2 drugs i know that needs such monitoring.

 

[leokitten]

Hi @leokitten I tend to agree with you to a degree, and you made sure to mention ‘under normal conditions’. However there are certain drugs that require careful monitoring such as lithium, tobramycin, gentamycin and others. Drugs that depend on a normal kidney and liver function will become toxic if these change, and it certainly can change. Valtrex and Valcyte are 2 drugs i know that needs such monitoring.

Very true, just had to simplify/summarize to not write an essay. Regarding Abilify it doesn’t require any specific monitoring other than carefully checking CYP interactions with others drugs you are taking or foods since it’s metabolized by CYP3A4 and 2D6.

 

[chelby]

@leokitten
Thankyou for explaining symptomatic tx vs disease modifying. I really appreciate it.

I was worried that symptomatic tx could mean masking PEM but know I understand you mean it targets downstream problems - so it could actually help PEM.

This does seem to be what is happening with abilify for me. Just got over PEM in 3hrs again from feeling quite horrible after going in a van to the park.

So, how would you describe the action of a drug like Ritalin that can create a false sense of energy and harm people with ME?

 

[leokitten]

So, how would you describe the action of a drug like Ritalin that can create a false sense of energy and harm people with ME?

Abilify isn’t a stimulant like methylphenidate or amphetamines. I believe stimulants can sometimes help with certain ME patients if they are very, VERY careful not to overdo it and dose just enough to improve symptoms enough while not masking PEM, etc. For example, they can be helpful for ME brain fog, cognitive impairment, concentration and focus symptoms that are not the same as adult ADD inattentive subtype but share some similarities.

But stimulants essentially just massively increase dopamine levels in the synaptic cleft of dopamine terminals in the striatum and prefrontal cortex, and this increases or decreases other neurotransmitter levels downstream. Dosing with stimulants can be difficult with ME because you don’t want to more negatively affect your sleep more than the horror ME already makes it.

But with Abilify it seems to be much more of a functionally selective regulator of dopamine and serotonin neurotransmission. This paper here discusses its mechanism of action mostly in reference to antipsychotic dosage levels, but still an interesting read

Update on the Mechanism of Action of Aripiprazole: Translational Insights into Antipsychotic Strategies Beyond Dopamine Receptor Antagonism

 

[leokitten]

I am microdosing with 0.25mg at morning and lunch time

You do not need to dose Abilify two times a day as it has a very long half life of 75-94 hours. Multiple daily dosing is only relevant for drugs with short half lives.

I looked up venlafaxine (Effexor) and it slightly inhibits CYP2D6, which is one of the two enzymes that metabolize Abilify. So good that you are microdosing at beginning. Make sure you check any metabolism interactions with other drugs you are taking.

New antidepressants and the cytochrome P450 system: focus on venlafaxine, nefazodone, and mirtazapine

 

[leokitten]

There’s also been discussion on the Abilify PR thread regarding its strong 5-HT7 serotonin receptor antagonism and this receptor’s role in immune system activation modulation in the brain (neuroinflammation)

 

[Braganca]

I starting microdosing Abilify a week ago and holy shit - it works!

How are you doing now @chelby?

I started abilify about a month ago at .25mg. First two weeks as I went from .25 up to .75, very bad worsening of symptoms. Bad insomnia, worse brain fog and vision, worse fatigue, some dizziness and nausea. Had to take a 4 day break in the second week. Restarted at .5mg. This time, no issues, no insomnia. Am now at 1,5mg.

Sadly, it’s not making me feel any better. I’m not worse though, continuing to tolerate fine. Hoping by the time I get to 2mg, and sustain it for a few weeks, I might see some benefits.

 

[chelby]

How are you doing now @chelby?

I started abilify about a month ago at .25mg. First two weeks as I went from .25 up to .75, very bad worsening of symptoms. Bad insomnia, worse brain fog and vision, worse fatigue, some dizziness and nausea. Had to take a 4 day break in the second week. Restarted at .5mg. This time, no issues, no insomnia. Am now at 1,5mg.

Sadly, it’s not making me feel any better. I’m not worse though, continuing to tolerate fine. Hoping by the time I get to 2mg, and sustain it for a few weeks, I might see some benefits.

I'm sorry to hear you haven't noticed positive effect.

I am still doing well. Bouncing back from PEM quicky, about a 5% increase in my baseline energy envelop and starting to see flashes of my personality come back.

Now I am on 0.5mg in the morning and 0.25mg at lunch. Neuro would like me to experiment with dosing and frequency up to 1.5mg. He said over that it might start to change dopamine as it does at therapeutic levels.

The insomnia i have been treating with doxylamine succinate which is an OTC pharmacy antihistamine. I am not sure how long it will remain effective.

I have also start 100mg Celebrex today in hope it could prolong the positive effects of the Abilify.

I am probably going to add mestinon in 2-3 weeks time as my POTS remains severe and my HR is still overly reactive to trivial movement and eating.

I am trying hard to remain careful and pace well bc it is very tempting to do activity now my muscle pain and feeling of PEM is lower.

 

[leokitten]

Here are a few possible mechanisms of action for Abilify which I searched against the ME neurological functional and structural evidence cataloged in this recent and good systematic review paper.

A systematic review of neurological impairments in myalgic encephalomyelitis/chronic fatigue syndrome using neuroimaging techniques (2020)


Cingulate cortex multiple dysfunctions in ME (cerebral blood flow, neuroinflammation, serotonin transporter deficiency, glucose hypomethylation, cognitive dysfunction, etc) : aripiprazole seems to increase regional cerebral blood flow and improve cognition to anterior cingulate cortex


The relationship between dopamine receptor blockade and cognitive performance in schizophrenia: a [11C]-raclopride PET study with aripiprazole

After switching from first-generation antipsychotics (FGA) such as haloperidol to aripiprazole, the blood-oxygen-level-dependent signal measured in the anterior cingulate cortex in patients with schizophrenia increased during cognitive function tasks21. They also showed performance improvement in memory, attention, and executive function tests after switching to aripiprazole22,23. Moreover, verbal cognitive function in patients improved after switching from second-generation antipsychotics and other FGAs to aripiprazole3,24.

Acute effects of single-dose aripiprazole and haloperidol on resting cerebral blood flow (rCBF) in the human brain

Further increases [in regional cerebral blood flow] were evident in the insula, hippocampus, and anterior cingulate after both antipsychotics

Hippocampus dysfunction and neuroinflammation in ME: aripiprazole appears to promote hippocampal growth and improve memory performance (though evidence is not robust)


The effect of second-generation antipsychotics on hippocampal volume in first episode of psychosis: longitudinal study

Aripiprazole subgroup displayed significant increases in bilateral hippocampal volume compared with all other subgroups

Bulking up the hippocampus in schizophrenia: a role for 5-HT1A agonists?

Although speculative, the agonist activity of aripiprazole at the 5-HT1A receptor may be relevant to its differential effect on hippocampal volume compared with other antipsychotic agents examined by Bodnar and colleagues. The 5-HT1A receptors are major inhibitory G-protein-coupled receptor subtypes found on pre- and post-synaptic neurons throughout the brain. They are highly expressed in brain regions implicated in affect regulation and memory processing, including the hippocampus, particularly in the CA1 region, the amygdala and in the frontal, cingulate and entorhinal cortices.11 5-HT1A receptors influence dopaminergic, cholinergic, glutamatergic and GABAergic functions. In this context, 5-HT1A receptor agonists have been considered as potentially pro-cognitive on the basis of preclinical evidence that they modulate the release of cortical and hippocampal dopamine and acetylcholine.11

Improving cognition in schizophrenia with antipsychotics that elicit neurogenesis through 5-HT(1A) receptor activation

Mechanisms by which hippocampal adult neurogenesis can be increased are therefore of therapeutic interest and a promising molecular target is the activation of serotonin 5-HT(1A) receptors because agonists at this site increase adult neuronal proliferation in the dentate gyrus. We hypothesize that use of antipsychotics possessing 5-HT(1A) receptor agonist properties may protect against or attenuate CIAS by a dual mechanism: a favorable influence on adult neurogenesis that develops upon sustained drug treatment, and an increase in dopamine levels in the prefrontal cortex that starts upon acute treatment.

Basal ganglia reduced activity and neuroinflammation in ME: one of aripiprazole's main mechanisms of action (in a very simplified and reductionist way) is that it stabilizes dysfunctional dopamine neuron firing and neurotransmission in a functionally selective way in the both the striatum and extrastriatal dopamine regions. Of course in reality it's more complex but not needed for this point. It's other main mechanisms of action at serotonin receptors also play there own part and interact with dopamine neurons.

Miller et al. [41] who described neuroinflammation as a potential mechanism underlying impaired neurotransmission in the basal ganglia. These features strongly suggest a neuroimmune process underlying ME/CFS pathology.

The cingulate cortex has strong reciprocal connections to the orbitofrontal cortex, the basal ganglia and the insula. The basal ganglia have important roles in reward-processing. Dysfunction of the basal ganglia has also been implicated in ME/CFS [41]. A fMRI study by Miller et al. [41] found that when performing a monetary gambling task, the right caudate and right globus pallidus were found to have significantly less activation in ME/CFS patient groups compared with HCs. The decreased activation detected in the right globus pallidus correlated with increased mental fatigue, general fatigue and reduced activity [41].

Decreased Basal Ganglia Activation in Subjects with Chronic Fatigue Syndrome: Association with Symptoms of Fatigue

Compared to non-fatigued controls, patients with CFS exhibited significantly decreased activation in the right caudate (p = 0.01) and right globus pallidus (p = 0.02). Decreased activation in the right globus pallidus was significantly correlated with increased mental fatigue (r2 = 0.49, p = 0.001), general fatigue (r2 = 0.34, p = 0.01) and reduced activity (r2 = 0.29, p = 0.02) as measured by the Multidimensional Fatigue Inventory. No such relationships were found in control subjects. These data suggest that symptoms of fatigue in CFS subjects were associated with reduced responsivity of the basal ganglia, possibly involving the disruption of projections from the globus pallidus to thalamic and cortical networks.

One mechanism that may contribute to alterations in function and neurotransmission in the basal ganglia in CFS is inflammation [47]. CFS patients have been shown to exhibit a number of immune alterations including the presence of increased inflammatory markers in the peripheral blood and increased production of inflammatory cytokines in ex vivo preparations of peripheral blood mononuclear cells [12]–[15]. As noted above, a number of inflammatory stimuli including the inflammatory cytokine, interferon alpha and cytokine inducers such as endotoxin and typhoid vaccination have been shown to alter basal ganglia function while also leading to symptoms of fatigue including psychomotor slowing and reduced motivation, both fundamental behavioral processes regulated by basal ganglia structures [19], [20], [47], [48].

TSPO-PET/MRI Reveals Increased Neuroinflammation in Basal Ganglia of Chronic Fatigue Syndrome Patients (prepublished)

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease affecting millions of people in the United States alone, but little is known about the underlying pathophysiology. We show that simultaneous TSPO-PET/MRI measurements using [11C]DPA-713, including SUV, SUVr, QSM, R2*, and volume can uncover new information about this disease. We find that the putamen has significantly higher TSPO-PET signal in ME/CFS subjects compared to healthy controls, indicating an elevated inflammatory response in this area. This finding corresponds to previous fMRI and diffusion imaging findings and may help with future diagnosis and tracking of this chronic, widespread disease.

Plus there are a number of published papers finding aripiprazole exhibits neuroprotective and anti-inflammatory effects in various areas of the brain (sorry too tired now to bring them into this post)

 

[leokitten]

Is anyone here on S4ME trialing Abilify, with or without potentially synergistic combos (COX-2 inhibitors, LDN)? On PR there are a number of people trialing the drug so just wondering.

 

[Braganca]

Is anyone here on S4ME trialing Abilify, with or without potentially synergistic combos (COX-2 inhibitors, LDN)? On PR there are a number of people trialing the drug so just wondering.

Yes.. several of us are trialing it. It’s discussed in this thread.

 

[Braganca]

I have been on abilify for 6 weeks. I went up to 2mg for a week, and am now back down at 1.5. It hasn’t helped me, really at all, in any dosage. Seemed to cause worsening of my symptoms the higher the dose.
Quite disappointing as nearly everyone else seems to have had success! May try adding in Celebrex to see if anything improves, if they are synergistic as some have reported. After that I will stop taking it.

 

[leokitten]

For those who have been taking Abilify and it’s giving significant improvements I guess it goes without saying, but people have reported you can still overexert and crash while on it. And I wonder like other treatments, if you crash enough times it will eventually stop working, who knows.

It can give quite significant ME symptom improvements and an increase in exertion capacity but of course it’s no panacea or cure. It reminds me of my experience during the beginning of doing keto. After 5 years of nothing working at all and slowly becoming housebound, once I went into ketosis the first time it was almost like a rush, my entire brain and body just rebooted and most ME symptoms melted away, it was like everything was clear and pre-illness again.

So my brain suddenly made me feel full of energy and like I could do anything, but some crucial part of ME pathophysiology is not corrected by keto. I started with my life again like I was fine and wanting to make up for lost time and then suddenly crash!

Keto made me recover quicker from crashes and extended my exertion capacity before PEM by a few days, but in a bad way it muted the signals that I was overdoing it and a few days isn’t like you can start living again it’s not as much capacity as it felt.

I ended up continuing to overexert and crash over and over again for many months. Even on keto the crashes caused the ME to get worse and change in a bad way that eventually keto stopped helping enough to outweigh the insane amount of work you have to put in stay in deep ketosis.

So I think the same goes with Abilify. I think it can help a great deal with whatever ME neurological and neuroinflammatory pathology is going on and your brain will wake up from the ME pain and haze, but like keto there are crucial aspects of ME it doesn’t help with and you have to consciously fight yourself to keep from overdoing even though you aren’t getting any signals.

I plan on trialing it, I’m just trying to figure out a conscious plan for how to control myself from overexerting if it does feel similar to how keto did in the beginning. Without signals it’s like you cannot control it, how do you tell yourself to proactively not live most of your life even if you feel more or less healthy like you can do anything?