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.