aripiprazole

[MD-psych]

Is aripirpazole more of a DA agonist at lower dose and vice-versa? If used for Bipolar or Psychosis, do we start at a higher dose; and not the usual "start low and go slow" approach? Thanks.

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[notdeadyet]

Is aripirpazole more of a DA agonist at lower dose and vice-versa? If used for Bipolar or Psychosis, do we start at a higher dose; and not the usual "start low and go slow" approach? Thanks.

If anything, because of its side effect profile, you can start abilify at a higher relative dose than some antipsychotics.

That said, because of efficacy, I think many of us only use Abilify if we are particularly concerned about side effect profiles on a particular patient and therefore start low, go slow with it. But in emergency cases inpatient with folks already on it who've been off meds for several months, I'm fine with giving 30 mg (with low dose benzo for akathisia). You can always taper after stabilizing, and it beats sacrificing safety.

 

[twright]

Surprisingly, in a recently published meta-analysis the use of aripiprazole as adjunctive treatment (for major depression) was associated with the same amount of weight gain as the other atypicals:
http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001403

And the evidence base for using aripiprazole as maintenance treatment for bipolar disorder is thin:
http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1000434

 

[MD-psych]

Thanks for the replies. However, I am trying to grasp whether, in a patient with hallucinations, a low dose would make things worse; given that it can (so I have been told) be more of a DA agonist at lower range?

 

[Shikima]

Worth a shot in my opinion, in general. But the question is, why this one?

 

[whopper]

Problems with Aripiprazole
Cost
Low efficacy
Relatively high amount of EPS- (I know. It's counter-intuitive being that it's a Da agonist).
As a depression augmentation agent, there's plenty of other far cheaper and safer choices. E.g. Buspirone, thyroid hormone, etc.

Benefits:
Low metabolic side effect profile
Sedation is unlikely (if that's what you're going for, making this not such a great choice for PRN agitation)
As a depression augmentation agent: FDA approval. Most of the meds out there that have this benefit don't have the FDA stamp, but this is not an area where I'd be concerned given the heavy amount of evidenced based data for the other augmentation agents.

When this medication first came out, I had high hopes the Da agonism would make it the curveball trick shot of antipsychotics. Here's what I'm talking about (remember, these were hopes).
1) It could work for patients where several other atypicals failed because it used a novel mechanism
2) This would be great for patients with EPS sensitivity
3) No fear of metabolic problems

All three of these have not panned out. It's not highly efficacious and I've had not one patient where this med worked when another didn't On the other hand I've had several patients where Risperdal, Zyprexa, or Clozapine worked where others have failed.

It causes more EPS than other atypicals. From personal experience and journal articles back this up, it's pretty much up there, almost with Risperdal.

It can cause some metabolic issues though it's no where near the concern in comparison with Clozapine or Zyprexa.

I have, however, noticed that it is a good choice for patients with first-break psychosis, or relatively weak psychosis that are compliant with meds and where avoidance of sedation is tantamount or already existing metabolic issues such as a college student that needs to pay attention in class, or a diabetic that's compliant on meds. This is not a population that you often see in the involuntary units, but more so in outpatient, has their act together, and failure of compliance is a low-concern.

 

[MD-psych]

Worth a shot in my opinion, in general. But the question is, why this one?

Given that it is hailed as one of the "weight neutral" antipsychotic.

 

[MD-psych]

Problems with Aripiprazole

quote]

Thanks for taking time to elaborate on this. I am curious to know if you have found any dose-dependent response to this medication?[/

 

[billypilgrim37]

I don't believe there is any data (or logic) to suggest abilify is a stronger agonist at lower doses and would worsen psychosis via dopaminergic pathways.

 

[whopper]

I don't believe there is any data (or logic) to suggest abilify is a stronger agonist at lower doses and would worsen psychosis via dopaminergic pathways.

You may be right and I'm not saying you are wrong. I have heard pharmacists mention the Da agonism is more at low dosaged and less at higher dosages and it then becomes just a plain D2 anatagonist.

The problem being that I never saw anything backing this up in a journal. When this medication first came out I was on the look out for articles better explaining this but as time went by, seeing what the medication did in real life sated my intellectual curiosity on that matter. Maybe the pharmacists I heard were right, but hearsay is a poor measure. Anyone know anything for real on this matter please write about it.

 

[digitlnoize]

When I choose it, it is largely due to its favorable lack of QTc prolongation. We use it fairly regularly in people who need an antipsychotic but are pushing the prolonged QT limit. Or were already doing well on it. Maybe I'd consider it more in a depression with psychosis patient who had failed other things. I'm not a big fan.
I think the practice of rx-ing dopamine blockers as depression adjuncts is suspect. I see Seroquel used this way a lot too, and it just bothers me. Seems counter-intuitive and grasping at straws. As whopper said, I'd much rather use thyroid or lithium or some other approved augmentation strategy. Hell, I'd go for Deplin (that hippie L-methylfolate stuff) over an antipsychotic.

 

[billypilgrim37]

You may be right and I'm not saying you are wrong. I have heard pharmacists mention the Da agonism is more at low dosaged and less at higher dosages and it then becomes just a plain D2 anatagonist.

I think this was the justification for why there was so much more akathisia at lower doses, but that's like how AZ says that Seroquel is NE uptake inhibitor as a mechanism for it being an AD (a quetiapine metabolite is, but the effect is so miniscule you'd need to take a lot more than we use clinically for THAT to be the mechanism of AD effect). There's an effect, so they have to make a plausible-sounding mechanism for it, even though it's rarely so simple and the proposed mechanism couldn't possibly account for the actual effect. That's nothing new. We told people for years that Prozac helped them because they had low 5HT, even though that didn't explain why it took 3-4 weeks to see effect most of the time. Abilify has the same pharmacology with D2 and suboxone has w/ mu opioid receptors, and you don't see addicts taking 0.5mg of suboxone to get high. Without enough occupancy I guess you could argue that the endogenous dopamine would not be competing much for open receptors while the Abilify would be latching on to a subset and agonizing receptors that otherwise would not be receiving endogenous dopamine, but that's a super stretch.

 

[michaelrack]

When abilify first came out I added it on to the medication regime of a few patients who were doing well on risperidone but had elevated prolactin levels- abilify drove the levels down to normal. This is a rather expensive strategy, but the combo might be worth looking at once abilify becomes generic.

 

[Red Beard]

Is aripirpazole more of a DA agonist at lower dose and vice-versa? If used for Bipolar or Psychosis, do we start at a higher dose; and not the usual "start low and go slow" approach? Thanks.

I believe it is incorrect/misleading to think of aripiprazole as having varying agonist or antagonist effects at different blood levels.

Aripiprazole is a partial agonist at any dose. It binds d2 and partially activates it, but does not produce the full conformational change in the receptor that endogenous dopamine would cause, so the activity is blunted. The more aripiprazole is present, the more d2 receptors get occupied by it, thus reducing the number of receptors available to bind dopamine. Net activity is reduced.

As for speed of titration, in an inpatient setting with a manic or psychotic patient, I would think you can (and should) titrate pretty quick as long as patient is tolerating it, like any antipsychotic. It is not a favored approach in the acute setting where I am training, so I can't say I've ever seen it work for these folks. I do have an outpatient with schizophrenia who (knock on wood) likes it quite a bit and has been asymptomatic on it now for nearly a year.

 

[whopper]

A pharmacist told me at dosages above 30 mg it acts as a D2 blocker, not as a partial agonist, but again, I've seen no journal articles on this.

Now back in the day, and this was something I wish still happened, back in the day where pharmaceutical rep dinners were common, the manufacturer of Aripiprazole had a pharmacist answer questions. Any questions I brought up that they couldn't answer, they looked up the answers and mailed them to me. In one of those printed letters, they told me what I mentioned above. IT was in print from the manufacturer. I did, however, toss that letter in the trash (hey how long you expect me to hold onto a letter?), expecting this to at some point be common knowledge. It's been years and I still haven't seen this data printed in a journal.

I think the practice of rx-ing dopamine blockers as depression adjuncts is suspect

The proposed theoretical mechanism isn't the D2 blockage but the 5HT2A blockage. In studies, it's the atypicals at low dosages that act at antidepressant augmentation agents and the typicals aren't having the same successes.

 

[splik]

Is aripirpazole more of a DA agonist at lower dose and vice-versa? If used for Bipolar or Psychosis, do we start at a higher dose; and not the usual "start low and go slow" approach? Thanks.

in the acute setting i would avoid using it in general because it's not very good. the reason to avoid the 'start low and go slow approach' is it would take months! abilify has a half-life of something like 75-94 hours so it doesn't make sense to increase the dose less than every few weeks. it is reasonable to give someone a lower dose to 'test' how they react, but in the acute setting i would whack them on at least 10mg or higher after tolerating a single 2.5mg dose.

 

[whopper]

Forgot to mention. There is data with almost any atypical at a low dosage having antidepressant augmentation benefit. This has been around for decades but the older atypicals such as Risperdal and Zyprexa never fought for an FDA approval.

The problem with Abilify as such an agent is that everyone is giving it out and it costs hundreds a month when several other meds also are augmentation agents for $4/month such as Buspirone.

 

[MD-psych]

Very informative replies. Yet, the lack of clear mechanism bugs me. Thank y'all very much for all your inputs, though.

 

[DebDynamite]

I had a case of acute dystonia a few weeks back and the patient was on aripiprazole. That got me to reading up about it quite a bit. You might find this interesting.


http://www.mdpsych.org/archive/03F_Sandson.htm

Perspectives on Psychopharmacology: Aripiprazole: Possibilities and Pitfalls
By Neil Sandson, MD

[Fall 2003; Vol. 30, No. 1; Pg 8, 12, 13]

Sample Case: DF is a 35 year-old male diagnosed with schizoaffective disorder, who had been stable for the past two years on a regimen of haloperidol, 10 mg qHS, ziprasidone, 80 mg b.i.d., and citalopram, 30 mg/d. Previous attempts to taper and discontinue the haloperidol had resulted in exacerbations of psychotic symptomatology. Due to concerns about eventually developing tardive dyskinesia, another attempt was made to transition from haloperidol, this time to aripiprazole. However, given his history of psychotic decompensations with the removal of haloperidol, the decision was made to titrate aripiprazole to the target dose and maintain it at this dose for at least one month before commencing the haloperidol taper. Aripiprazole was started at 10 mg/d. Over the next seven days, the patient became increasingly agitated and aggressive, with an increase in paranoia and auditory hallucinations. Ten days after starting the aripiprazole, the dose was increased to 15 mg/d. However, he continued to decompensate over the next several days, eventually requiring hospitalization. Once he was hospitalized, the aripiprazole was discontinued. Three days after stopping the aripiprazole, his agitation, aggression, and psychotic symptoms began to remit. He eventually reachieved his more functional baseline three weeks after the aripiprazole was discontinued. There were no obvious acute stressors which preceded this decompensation, and he was known to be compliant with his medications. Throughout the above sequence of events, there were no changes in any of his other medications.

Considering how long psychiatrists have been treating patients with psychotic disorders, we still achieve only modest success. The first generation of antipsychotic agents has relied purely on blockade of the dopamine type 2 (D2) receptor to provide clinical efficacy. These agents have provided reasonable control of psychotic symptoms, but at the cost of extrapyramidal side-effects and a host of other noxious symptoms (hyperprolactinemia, anhedonia, constipation, weight gain, sedation, etc.). The next generation of antipsychotics has displayed less robust blockade of the D2 receptor combined with blockade of serotonin type 2A receptors. While these factors have led to improved tolerability of these newer agents, they have not provided any true improvements in efficacy. The sole exception to this generalization is clozapine, which has provided greater benefit to treatment resistant patients than its fellow “atypicals”. However, this is a “high maintenance” drug to use. Hence, we eagerly await, and readily employ, any new antipsychotic options which become available.

Aripiprazole is the most recent addition to our antipsychotic armamentarium. It employs a mechanism of action quite different from any of the typical or atypical agents which have preceded it. Aripiprazole is a partial dopamine agonist. When it occupies the D2 receptor, it agonizes this receptor with, according to some estimates, at least 25% of the pharmacodynamic activity of endogenous dopamine1. In the mesolimbic pathway, where excessive dopaminergic tone is thought to account for positive psychotic symptoms, this agent acts as a gentle dopamine antagonist relative to this excessive dopamine activity. However, in the nigra-striatal and tuberoinfundibular pathways, where dopamine antagonism may produce EPS and hyperprolactinemia, this agent produces neither because it is not a dopamine antagonist, just a less robust agonist than endogenous dopamine.

At first glance, this is a very appealing drug, and for good reason. It provides the promise of efficacy without the EPS of the typical agents and without the weight gain, diabetes, and cardiac conduction related concerns of many of the “atypical” agents. It would seem to represent a possible new generation of antipsychotic medication. Theoretically, it might capture a subset of psychotic patients who have been poorly responsive to all the other antipsychotic agents. However, early clinical experience with aripiprazole has produced some confusing and disappointing results in specific cases. When the receptor occupancy profile of this drug is examined further, some of these results become easier to understand. While this is a straightforward, well-tolerated, and effective drug to use as antipsychotic monotherapy, attempts to combine aripiprazole with other antipsychotics, even transiently, create exceptional complexity and pose unique challenges to the clinician. Failure to recognize, anticipate, and appropriately respond to these unique challenges may lead to psychotic relapses as seen in the initial case example.

Aripiprazole actually possesses two unusual properties with respect to dopaminergic function in the brain. The first is its partial dopamine agonist profile. The second property is not as widely recognized, but it is no less important. Basically, aripiprazole binds to the D2 receptor far more avidly than any other commonly used antipsychotic. The package insert for aripiprazole lists a binding coefficient of 0.34 nM2, where smaller numbers denote tighter binding. Thus, aripiprazole binds to the D2 roughly twice as avidly as haloperidol (0.7 nM)3 and almost 1000 times more avidly than quetiapine (329 nM)4.

Let’s explore the implications of these figures. With a half-life of roughly 72 hours, this drug reaches steady state in the CNS in about 2 weeks. Let us take the example of a patient who enjoys a good antipsychotic response from haloperidol, but who wishes to switch to aripiprazole to eliminate EPS or hyperprolactinemia. For the purposes of this illustration, let us assume that there will be equal concentrations of haloperidol and aripiprazole in the CNS at steady state. If aripiprazole is added to haloperidol in a crossover titration, then the initiation of steady state for aripiprazole would effectively displace 66.7% of the haloperidol molecules from the D2 receptors in the various dopamine pathways of the brain. Since aripiprazole has only just reached steady state by day 14, it has not yet had time to exert its own clinical efficacy, which might be expected to occur in an additional two weeks. However, aripiprazole’s displacement of haloperidol from D2 receptors by this time creates a vulnerable window during which relapse is much more likely to occur.

As “bossy” as aripiprazole seems in this crossover, it is vastly worse when aripiprazole is added to an “atypical” agent. While the effect of haloperidol in the example above is attenuated by displacement from D2 and altered in a confusing and unpredictable manner by aripiprazole’s partial agonism, the contribution of haloperidol is probably not lost altogether, just significantly reduced. However, when aripiprazole is added to an “atypical” agent and steady state is achieved, the atypical then exerts virtually no meaningful influence as far as the D2 receptor is concerned. Essentially, adding aripiprazole to another antipsychotic automatically creates an on-off mode of crossover titration. Aripiprazole does not allow the clinician to effectively adopt a conservative mode of crossover titration in which the original agent is not tapered until the new agent has been at a steady state blood level for several weeks. Rather, aripiprazole effectively completes the crossover as it approaches steady state, or even earlier.

The above discussion begs the question of how to safely and effectively introduce aripiprazole to a regimen in which a partial or full response to another antipsychotic is already underway. Unfortunately, there is, as yet, no clearly “right” answer. A theoretically possible, but somewhat unattractive option, would be to increase the dose of the original agent in anticipation of adding aripiprazole, to compensate for its displacement effect at the D2 receptor. Another potential solution would be to initiate aripiprazole at a lower than recommended dose in such cases. Aripiprazole does come in 10 mg tablets which are scored. This conveniently allows for starting doses as low as 5 mg/d, which may then be gradually titrated to the usual target dose of 15 mg/d. However, this method runs the risk of accomplishing displacement of the original antipsychotic from the D2 receptor while further delaying the onset of aripiprazole’s therapeutic actions – the worst of both worlds. A third option is to perform standard conservative crossover titrations, but to be especially vigilant regarding the need for PRN medications (typical agents, benzodiazepines, etc.) during the vulnerable interval. Whatever course one selects, the likelihood for success in switching to aripiprazole will be considerably enhanced if there is an active awareness of these potential difficulties, and a readiness to address these difficulties should they arise.

Whether using aripiprazole as monotherapy or adding it to another antipsychotic, 15 mg/d is generally thought to be an appropriate initial target dose unless an inducer of cytochrome P450 3A4 is present (carbamazepine, phenytoin, St. John’s wort, etc.), in which case a target dose of 30 mg/d would be more appropriate.

References

1 Burris KD, Molski TF, Xu C, et al: Aripiprazole, a novel antipsychotic, is a high-affinity partial agonist at human dopamine D2 receptors. J Pharmacol Exp Ther 302(1):381-9, 2002.

2 Abilify package insert, Otsuka Pharmaceutical Co, Ltd, Tokyo, Japan, November 2002.

3 Bymaster FP, Calligaro DO, Falcone JF, et al: Radioreceptor binding profile of the atypical antipsychotic olanzapine. Neuropsychopharmacology 14(2):87-96, 1996.

4 Seroquel package insert, AstraZenica Pharmaceuticals LP, Wilmington, DE, 2001.

5 Casey DE, Carson WH, Saha AR, et al: Switching patients to aripiprazole from other antipsychotic agents: a multicenter randomized study. Psychopharmacology 166(4):391-9, 2003.

Neil Sandson, M.D. is the Director of the Division of Education and Residency Training for the Sheppard Pratt Health System, where he also directs the Psychopharmacology Consultation Service. He is also a Clinical Assistant Professor in the Department of Psychiatry at the University of Maryland Medical System. He is the author of a book entitled “Drug Interactions Casebook: The Cytochrome P450 System and Beyond”, American Psychiatric Publishing Inc., May 2003.

 

[DebDynamite]

Yes, it's eleven years old, but the point is worth noting. I have also seen spikes in lipid panels after starting some, but not all pts on aripiprazole. I rarely start it these days.

 

[PistolPete]

Very interesting case discussion centering on Abilify, thank you!