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• Aripiprazole may interact preferentially with distinct conformations of the D2 receptor, leading to a spectrum of pharmacologic effects, including acting as a full agonist, partial agonist, or antagonist.
• Clinical predictors of aripiprazole-associated worsening of psychosis include low baseline level of psychopathology and previous treatment with high-dose antipsychotics.
• Rapid transition from a medication with significant anticholinergic properties to 1 without these properties may result in symptoms of activation, including restlessness, insomnia, and anxiety, which can be mistaken for worsening psychosis.
• Akathisia, a common adverse effect of aripiprazole, may masquerade as treatment-emergent worsening of psychotic symptoms.
Mr. N, age 29, presents to the emergency department at the urging of his family because of poor self-care, bizarre behavior, and disturbed sleep. He first experienced psychiatric symptoms 10 years ago after his mother died. He became dysphoric and paranoid, displaying bizarre responses and behaviors with poor self-care and a gradual functional decline. He has been taking sertraline, 100 mg/d, for 10 years.
Upon arrival at the hospital’s inpatient unit, Mr. N is unkempt, oddly related, and paranoid. His affect is constricted. Mr. N displays thought blocking and possibly is responding to internal stimuli. Sertraline is continued and haloperidol, 1 mg/d, is initiated. For the next 2 weeks, Mr. N continues to be oddly related, irritable, and paranoid, and experiences disturbed sleep and thought blocking. After an episode of impulsive aggression, the treatment team initiates aripiprazole, which is titrated to 30 mg/d for 1 week. Mr. N’s clinical status worsens; he is menacing toward other patients and his thinking is more disorganized, with loose associations and ideas of reference. He requires 4 injections of IM haloperidol, 5 mg, and several visits to the seclusion room over the next week. Haloperidol is increased to 30 mg/d over the next 10 days, then aripiprazole is discontinued because of a putative drug interaction with haloperidol. Following the medication changes Mr. N demonstrates better behavioral control, but still is grossly psychotic. While awaiting transfer to a state hospital, Mr. N receives a trial of olanzapine, 20 to 40 mg/d, for 2 weeks without significant benefit.
Several clinical trials demonstrate a significant reduction in intensity of psychotic symptoms with aripiprazole, which has a unique mechanism of action.1 However, since its FDA approval in 2002, several case reports have described treatment-emergent psychotic symptoms associated with aripiprazole initiation. Over the past 40 years, reports of worsening psychosis associated with antipsychotics have been limited to patients with schizophrenia who were taking high dosages or who had high plasma concentrations, when anticholinergic delirium may have explained increased psychotic symptoms.2-4
How can a drug effectively treat psychotic symptoms and occasionally worsen them? In this article, we discuss the relevant pharmacology and clinical literature on aripiprazole and try to make sense of this apparent paradox.
Unique pharmacologic profile
Antipsychotics have been reported to be either neutral antagonists or inverse agonists at the D2 receptor, based on in vitro data.5 Aripiprazole and its main metabolite, dehydroaripiprazole, originally were described as partial agonists at D2 dopamine receptors.6,7 However, it appears aripiprazole’s pharmacologic action is better explained by the concept of functional selectivity. Aripiprazole may interact preferentially with distinct conformations of the D2 receptor, leading to a spectrum of pharmacologic effects, including acting as a full agonist, partial agonist, or antagonistic.5
Researchers have hypothesized that the pathophysiology of schizophrenia may, in part, be caused by dysfunction of mesocorticolimbic dopaminergic neurons characterized by an enhanced sensitivity of postsynaptic D2 receptors and increased sensitivity to dopaminergic drugs.8,9 In addition, chronic treatment with a D2 receptor antagonist is associated with increases in postsynaptic dopamine receptor density (ie, an increase in receptor reserve).10,11 Upregulation of D2 receptors may explain several features seen in patients chronically treated with antipsychotics, including tardive dyskinesia12 and rapid psychotic relapse after discontinuing an antipsychotic (supersensitivity psychosis).13 Because chronic antipsychotic treatment leads to high postsynaptic receptor reserve, aripiprazole initiation may produce overactivation of D2 receptors, which might worsen a patient’s condition.14 In vitro data15-18 and clinical observations indicate that aripiprazole has intrinsic efficacy at D2 receptors, as do clinical observations, such as:
- its propensity to reduce serum prolactin19
- a decreased likelihood of producing extrapyramidal side effects despite >80% occupancy of D2 receptors6
- case reports documenting aripiprazole-associated mania,20 improvement of risperidone-associated cognitive impairment,21 and pathologic gambling.22
Emergence or worsening of psychotic symptoms or a marginal antipsychotic effect may occur if aripiprazole is indeed a postsynaptic D2 receptor agonist. An individual patient’s outcome likely would depend on his or her sensitivity to psychosis and concurrent or previous exposure to a D2 receptor antagonist. For example, stimulation of postsynaptic D2 receptors may be further augmented if the dosage of the previous antipsychotic was reduced or withdrawn before initiating aripiprazole because additional receptors would be available for interaction with aripiprazole.
Case reports
A literature review revealed 23 reports of treatment-emergent psychosis associated with aripiprazole initiation (Table). The mean age of the patients was 47 (range: 17 to 69) and 57% were men. Most patients (87%) were diagnosed with a schizophrenia-spectrum illness before aripiprazole initiation. Most (57%) had mild, stable, or no psychotic symptoms before aripiprazole initiation. Most were receiving relatively high doses of antipsychotics (average chlorpromazine equivalents [CPZE]: 648 mg/d) before aripiprazole initiation. This medication was either decreased or discontinued in 70% of patients.
Emergence or worsening of psychotic symptoms included agitation, aggressive behavior, and increased psychomotor activity. However, akathisia evaluation was described in only 2 reports: 1 author identified akathisia symptoms, but attributed them to a concomitant antipsychotic (fluphenazine)23 and the other report specifically excluded the possibility of akathisia.24 Two systematic studies have attempted to establish risk factors for aripiprazole-associated worsening psychosis (Box).14,25
In our literature review, the mean final dose of aripiprazole was 21.5 mg/d (range: 2 to 60 mg/d). In the cases describing subsequent treatment, all but 1 patient were switched to another antipsychotic, including 2 whose psychotic symptoms stabilized with continuation of aripiprazole and addition of a second antipsychotic. Interestingly, in the case reported by Adan-Manes et al,26 initial treatment with aripiprazole monotherapy was efficacious, but a subsequent trial of adjunctive aripiprazole resulted in worsening psychosis.
Table
Case reports: Treatment-emergent psychosis associated with aripiprazole
| Study | Age, sex | Diagnosis | Before aripiprazole initiation | Pre-aripiprazole treatment | Aripiprazole dose | Concomitant psychotropic treatment | Subsequent treatment |
|---|---|---|---|---|---|---|---|
| Chiu et al, 2011a | 39, M | Schizophrenia | Psychiatrically stable, tardive dystonia | Clozapine, 300 mg/d | 10 mg/d | Valproic acid, 1,000 mg/d, clonazepam, 2 mg/d, mephenoxalone, 800 mg/d | Clozapine |
| Ekinci et al, 2010b | 17, M | ADHD | Inattention and impulsive aggression | Tapered and discontinued risperidone, 2.5 mg/d | 5 mg/d | Methylphenidate, 54 mg/d | Risperidone, 2 mg/d, methylphenidate, 36 mg/d |
| Selvaraj et al, 2010c | 49, F | Chronic depression | Depressive symptoms, suicidal ideation | None stated | 2 mg/d | Duloxetine, 80 mg/d, clonazepam, 2 mg/d | Duloxetine, 120 mg/d |
| Adan-Manes et al, 2009d | 23, M | Schizophrenia | No psychotic symptoms | Abrupt decrease of amisulpride dose from 800 mg/d to 400 mg/d | 20 mg/d | Biperiden, 4 mg/d | Amisulpride, 800 mg/d |
| Cho et al, 2009e | 45, F | Schizophrenia | Persistent psychotic symptoms, new onset diabetes with acute ketoacidosis | Haloperidol, 20 mg/d, abrupt clozapine discontinuation | 15 mg/d | Valproic acid, nortriptyline | Molindone, 150 mg/d |
| Ahuja et al, 2007f | 35, F | Schizoaffective disorder | Stable before medication change | Tapered amisulpride, 400 mg/d, over 6 weeks | 15 mg/d | None | Amisulpride, 600 mg/d |
| Lea et al, 2007g | 57, M | Schizophrenia | Persistent psychotic symptoms, treatment resistance, recent recovery from NMS | Discontinued ziprasidone, 200 mg/d | 30 mg/d | Lorazepam, 2 mg/d, amantadine, 100 mg, sertraline, 50 mg/d | Clozapine |
| Lea et al, 2007g | 49, M | Schizoaffective disorder | Delusions, verbal aggression, substance abuse, HCV | Decreased quetiapine dose from 800 mg/d to 400 mg/d | 15 mg/d | Divalproex, 1,000 mg/d, fluvoxamine, 200 mg/d, clonazepam, 2 mg/d | Lithium, quetiapine, 500 mg/d, haloperidol, 2 mg/d |
| Lea et al, 2007g | 60, M | Schizophrenia | Delusions, labile mood, aggression | Risperidone, 3 mg/d, interruption of fluphenazine, 75 mg/d | 20 mg/d | Divalproex, 4,500 mg/d, benztropine, 3 mg/d | Not discussed |
| Raja, 2007h | 30, M | Schizoaffective disorder | Negative symptoms, otherwise stable, recent citalopram discontinuation | Discontinued amisulpride, 800 mg/d over 2 weeks | 30 mg/d | Lithium | Amisulpride, 500 mg/d |
| Raja, 2007h | 69, F | Bipolar disorder | History of multiple relapses; presented with tremor, akathisia, weight gain | Discontinued risperidone, 2 mg/d, over 2 weeks | 15 mg/d | Lithium | Risperidone, 4 mg |
| Raja, 2007h | 59, F | Schizophrenia | Negative symptoms, otherwise stable | Reduced risperidone dosage from 5 mg/d to 4 mg/d | 7.5 mg/d | None | Risperidone, 5 mg/d |
| Thone, 2007i | 31, M | Schizophrenia | Confusion, agitation, delusions worsened with aripiprazole dose increase | None | 60 mg/d | None | Aripiprazole dose reduction to 15 mg/d, olanzapine, 10 mg/d |
| Glick et al, 2006j | 55, F | Schizophrenia | Stable before medication change | Tapered and discontinued thioridazine, 600 mg/d, over 3 months | 30 mg/d | None | Chlorpromazine, 200 mg/d, aripiprazole, 30 mg/d |
| Glick et al, 2006j | 52, M | Schizophrenia | Negative symptoms | Decreased olanzapine dose from 30 mg/d to 20 mg/d | 30 mg/d | None | Olanzapine, 30 mg/d |
| Barnas et al, 2005k | 57, F | Schizoaffective disorder | Stable before medication change | Discontinued perphenazine, 8 mg/d | 30 mg/d | None | Quetiapine, 350 mg/d |
| DeQuardo, 2004l | 54, M | Schizophrenia | History of aggression, residual paranoia, severe EPS | Haloperidol, 200 mg/d | 15 mg/d | Benztropine | Haloperidol |
| DeQuardo, 2004l | 51, M | Schizophrenia | History of aggression, persistent psychotic symptoms, treatment resistance | Olanzapine, 60 mg/d | 10 mg/d | None | Olanzapine |
| Ramaswamy et al, 2004m | 43, F | Schizoaffective disorder | Psychiatrically stable, multiple medication changes, including substituting carbamazepine for valproic acid | Discontinued ziprasidone, 160 mg/d, discontinued quetiapine, 400 mg/d, over 2 weeks | 30 mg/d | Propranolol, 30 mg/d, l-thyroxine, .05 mg/d, carbamazepine, 600 mg/d | Not available |
| Ramaswawamy et al, 2004m | 57, F | Schizoaffective disorder | History of multiple hospitalizations, but stable before medication change | Decreased olanzapine dose from 20 mg/d to 15 mg/d | 30 mg/d | Valproic acid, 2,000 mg/d | Ziprasidone |
| Ramaswawamy et al, 2004m | 67, F | Schizophrenia | Remote hospitalizations, recent worsened psychosis | Decreased ziprasidone dose from 200 mg/d to 160 mg/d 2 months previously | 30 mg/d | Carbamazepine, 200 mg/d | Not discussed |
| Ramaswamy et al, 2004m | 46, M | Schizophrenia | Persistent delusions while receiving risperidone, TD | Risperidone, 3 mg/d | 15 mg/d | Valproic acid, 1,500 mg/d | Risperidone, 3 mg/d |
| Reeves et al, 2004n | 50, M | Schizoaffective disorder | Relatively stable with nonthreatening delusions, hallucinations | Quetiapine, 800 mg/d | 30 mg/d | Divalproex, 2,000 mg/d | Olanzapine, 20 mg/d |
| ADHD: attention-deficit/hyperactivity disorder; EPS: extrapyramidal symptoms; HCV: hepatitis C virus; NMS: neuroleptic malignant syndrome; TD: tardive dyskinesia Source: References a. Chiu YH, Chen CH, Lu ML. Worsening psychosis after adding aripiprazole to clozapine. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35(1):291-292. b. Ekinci O, Sabuncuoglu O. Psychosis associated with switching from risperidone to aripiprazole in an adolescent on methylphenidate treatment. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35(2):648-649. c. Selvaraj V, Ramaswamy S, Sharma A, et al. New-onset psychosis and emergence of suicidal ideation with aripiprazole. Am J Psychiatry. 2010;167(12):1535-1536. d. Adan-Manes J, Garcia-Parajua P. Aripiprazole in combination with other antipsychotic drugs may worsen psychosis. J Clin Pharm Ther. 2009;34(2):245-246. e. Cho DY, Lindenmayer JP. Aripiprazole-induced agitation after clozapine discontinuation: a case report. J Clin Psychiatry. 2009;70(1):141-143. f. Ahuja N, Lloyd AJ. Aripiprazole and worsening of psychosis: a case report. J Clin Psychiatry. 2007;68(5):805-806. g. Lea JW, Stoner SC, Lafollette J. Agitation associated with aripiprazole initiation. Pharmacotherapy. 2007;27(9):1339-1342. h. Raja M. Improvement or worsening of psychotic symptoms after treatment with low doses of aripiprazole. Int J Neuropsychopharmacol. 2007;10(1):107-110. i. Thone J. Worsened agitation and confusion in schizophrenia subsequent to high-dose aripiprazole. J Neuropsychiatry Clin Neurosci. 2007;19(4):481-482. j. Glick ID, Duggal V, Hodulik C. Aripiprazole as a dopamine partial agonist: positive and negative effects. J Clin Psychopharmacol. 2006;26(1):101-103. k. Barnas ME, Hussain N, Petrides G. Treatment-emergent psychosis with aripiprazole. J Clin Psychiatry. 2005;66(10):1339. l. DeQuardo JR. Worsened agitation with aripiprazole: adverse effect of dopamine partial agonism? J Clin Psychiatry. 2004;65(1):132-133. m. Ramaswamy S, Vijay D, William M, et al. Aripiprazole possibly worsens psychosis. Int Clin Psychopharmacol. 2004;19(1):45-48. n. Reeves RR, Mack JE. Worsening schizoaffective disorder with aripiprazole. Am J Psychiatry. 2004;161(7):1308. | |||||||
Takeuchi et al14 aimed to establish predictors of worsening psychosis in a naturalistic setting where patients slowly transitioned to aripiprazole from previous antipsychotic treatment. Patients were required to be on a stable dose of an antipsychotic before participating in the study. Aripiprazole was started at 12 mg/d for 2 weeks with flexible dosing from weeks 2 to 52. Previous antipsychotic therapy was reduced biweekly by 25%. The incidence of worsening psychopathology after aripiprazole initiation was higher in the group of patients who had previously received high-dose antipsychotic therapy (average chlorpromazine equivalents [CPZE]: 727 mg/d) compared with the group on low dosages (average CPZE: 382 mg/d). It is possible that previous high-dose antipsychotic therapy was indicative of more significant baseline psychopathology; however, the worsened group and stabilized group had similar baseline Clinical Global Impressions-Severity scores.
Pae et al25 aimed to find predictors of worsening psychosis with aripiprazole in patients whose previous antipsychotic therapy was immediately discontinued. They found lower baseline disease severity was associated with significant worsening during the first month of aripiprazole treatment.
Other potential explanations
Aripiprazole’s manufacturer reported the incidence of psychosis-related adverse events in an analysis of 9 randomized schizophrenia trials.27 The rates of psychosis-related adverse events ranged from 0.6% to 18%, but there was no apparent relationship to study design or method of transitioning to aripiprazole. Rates of psychosis-related adverse events were similar between aripiprazole and the control group (placebo in 3 studies, another antipsychotic in 2 studies).
Emergence or worsening of psychotic symptoms temporally associated with aripiprazole initiation does not necessarily imply causation. As in Mr. N’s case, it is not always possible to determine whether worsening psychosis is the natural disease course or a treatment effect. In addition, it is not possible to differentiate lack of efficacy from a true propensity for aripiprazole to worsen psychosis.
It also is conceivable discontinuation or dosage reduction of a previous antipsychotic would worsen psychotic symptoms or cause side effects. When significant changes in psychopathology or side effects develop during the transition from 1 antipsychotic to another, it is difficult to determine etiology. Specifically, rapid transition from a medication with significant anticholinergic and antihistaminic properties—such as quetiapine or olanzapine—to 1 without these properties—such as aripiprazole—may result in symptoms of activation, including restlessness, insomnia, and anxiety. Consequently, these symptoms could be mistaken for worsening psychosis.28 Only 1 patient in this series was reported to abruptly discontinue an antipsychotic with significant anticholinergic properties (clozapine) before initiating aripiprazole.24 Studies by Takeuchi et al14 and Pae et al25 did not report the relative baseline use of antipsychotic medication with anticholinergic properties.
In a pooled analysis of treatment-emergent adverse events in 5 randomized clinical trials of patients receiving aripiprazole for acute relapse of schizophrenia, the incidence of akathisia was 10%, although it is not clear if this is a dose-related adverse effect.29 Because akathisia may be confused for worsening psychosis,30 it is possible akathisia was mistakenly identified as worsening psychotic symptoms in Mr. N’s case, as well as several reports from our literature review.
Covert akathisia is unlikely to explain worsening psychopathology observed in all patients in our literature review because confusion of akathisia and worsening psychosis is not a widespread phenomenon. In a post hoc analysis of pooled safety data from aripiprazole trials, Kane et al31 did not find a correlation between presence of akathisia and aripiprazole efficacy as measured by the Positive and Negative Syndrome Scale (PANSS) total, PANSS positive, PANSS negative, Clinical Global Impressions-Severity, Clinical Global Impressions-Improvement, and percentage of responders. Pae et al25 also noted there was no correlation between scores on the Barnes Akathisia Rating Scale and worsening psychopathology in patients switched to aripiprazole.
An antagonist always is an antagonist and clinicians have appreciated this concept since the days of chlorpromazine. The activity of aripiprazole, however, is on a pharmacologic continuum between a neutral antagonist and full agonist and currently there is no way to precisely determine the level of D2 receptor agonist action in a patient.
Although it is interesting to speculate that aripiprazole’s D2 receptor agonist action may contribute to worsening psychosis,32-34 there are other plausible explanations to consider. Rapid transition from a drug with significant anticholinergic properties and aripiprazole-associated akathisia may contribute to worsening psychopathology in patients starting aripiprazole. Because covert side effects may be incorrectly identified as psychotic agitation, we cannot exclude this as a possible etiologic factor in Mr. N’s case as well as the cases in our literature review.
Related Resource
- Abilify [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2011.
Drug Brand Names
- Amantadine • Symmetrel
- Aripiprazole • Abilify
- Benztropine • Cogentin
- Biperiden • Akineton
- Carbamazepine • Tegretol
- Chlorpromazine • Thorazine
- Clonazepam • Klonopin
- Clozapine • Clozaril
- Divalproex • Depakote
- Duloxetine • Cymbalta
- Fluphenazine • Permitil, Prolixin
- Fluvoxamine • Luvox
- Haloperidol • Haldol
- Lithium • Eskalith, Lithobid
- Lorazepam • Ativan
- Nortriptyline • Aventyl, Pamelor
- Methylphenidate • Concerta
- Molindone • Moban
- Olanzapine • Zyprexa
- Perphenazine • Trilafon
- Propranolol • Inderal
- Quetiapine • Seroquel
- Risperidone • Risperdal
- Sertraline • Zoloft
- Thioridazine • Mellaril
- Thyroxine • Synthroid
- Valproic acid • Depakene
- Ziprasidone • Geodon
Disclosure
The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.
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2. Chong SA, Tan CH, Lee HS. Worsening of psychosis with clozapine and selective serotonin reuptake inhibitor combination: two case reports. J Clin Psychopharmacol. 1997;17(1):68-69.
3. Bowers MB Jr, Swigar ME. Psychotic patients who become worse on neuroleptics. J Clin Psychopharmacol. 1988;8(6):417-421.
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6. Grunder G, Carlsson A, Wong DF. Mechanism of new antipsychotic medications: occupancy is not just antagonism. Arch Gen Psychiatry. 2003;60(10):974-977.
7. Wood MD, Scott C, Clarke K, et al. Aripiprazole and its human metabolite are partial agonists at the human dopamine D2 receptor, but the rodent metabolite displays antagonist properties. Eur J Pharmacol. 2006;546(1-3):88-94.
8. Seeman P, Weinshenker D, Quirion R, et al. Dopamine supersensitivity correlates with D2High states, implying many paths to psychosis. Proc Natl Acad Sci U S A. 2005;102(9):3513-3518.
9. Seeman P, Ko F, Jack E, et al. Consistent with dopamine supersensitivity, RGS9 expression is diminished in the amphetamine-treated animal model of schizophrenia and in postmortem schizophrenia brain. Synapse. 2007;61(5):303-309.
10. Burt DR, Creese I, Snyder SH. Antischizophrenic drugs: chronic treatment elevates dopamine receptor binding in brain. Science. 1977;196(4287):326-328.
11. Silvestri S, Seeman MV, Negrete JC, et al. Increased dopamine D2 receptor binding after long-term treatment with antipsychotics in humans: a clinical PET study. Psychopharmacology (Berl). 2000;152(2):174-180.
12. Sayers AC, Bürki HR, Ruch W, et al. Neuroleptic-induced hypersensitivity of striatal dopamine receptors in the rat as a model of tardive dyskinesias. Effects of clozapine, haloperidol, loxapine and chlorpromazine. Psychopharmacologia. 1975;41(2):97-104.
13. Moncrieff J. Does antipsychotic withdrawal provoke psychosis? Review of the literature on rapid onset psychosis (supersensitivity psychosis) and withdrawal-related relapse. Acta Psychiatr Scand. 2006;114(1):3-13.
14. Takeuchi H, Uchida H, Suzuki T, et al. Predictors of clinical worsening after a switch to aripiprazole in patients with schizophrenia: a 1-year naturalistic follow-up study. J Clin Psychopharmacol. 2009;29(4):394-395.
15. Shapiro DA, Renock S, Arrington E, et al. Aripiprazole, a novel atypical antipsychotic drug with a unique and robust pharmacology. Neuropsychopharmacology. 2003;28(8):1400-1411.
16. Urban JD, Vargas GA, von Zastrow M, et al. Aripiprazole has functionally selective actions at dopamine D2 receptor-mediated signaling pathways. Neuropsychopharmacology. 2007;32(1):67-77.
17. Klewe IV, Nielsen SM, Tarpo L, et al. Recruitment of beta-arrestin2 to the dopamine D2 receptor: Insights into anti-psychotic and anti-parkinsonian drug receptor signaling. Neuropharmacology. 2008;54(8):1215-1222.
18. Masri B, Salahpour A, Didriksen M, et al. Antagonism of dopamine D2 receptor/beta-arrestin 2 interaction is a common property of clinically effective antipsychotics. Proc Natl Acad Sci U S A. 2008;105(36):13656-13661.
19. Shim JC, Shin JG, Kelly DL, et al. Adjunctive treatment with a dopamine partial agonist, aripiprazole, for antipsychotic-induced hyperprolactinemia: a placebo-controlled trial. Am J Psychiatry. 2007;164(9):1404-1410.
20. Padala PR, Wengel SP, Petty F. Manic episode during treatment with aripiprazole. Am J Psychiatry. 2007;164(1):172-173.
21. Hu CH, Pai N, Huang XF, et al. Potential control of risperidone-related cognitive deficits by adjunctive aripiprazole treatment. J Clin Psychopharmacol. 2011;31(1):135-136;author reply 136–137.
22. Cohen J, Magalon D, Boyer L, et al. Aripiprazole-induced pathological gambling: a report of 3 cases. Curr Drug Saf. 2011;6(1):51-53.
23. Lea JW, Stoner SC, Lafollette J. Agitation associated with aripiprazole initiation. Pharmacotherapy. 2007;27(9):1339-1342.
24. Cho DY, Lindenmayer JP. Aripiprazole-induced agitation after clozapine discontinuation: a case report. J Clin Psychiatry. 2009;70(1):141-143.
25. Pae CU, Chiesa A, Mandelli L, et al. Predictors of early worsening after switch to aripiprazole: a randomized, controlled, open-label study. Clin Drug Investig. 2010;30(3):187-193.
26. Adan-Manes J, Garcia-Parajua P. Aripiprazole in combination with other antipsychotic drugs may worsen psychosis. J Clin Pharm Ther. 2009;34(2):245-246.
27. Cognata-Smith C, Baker RA, Pikalov A, et al. Analysis of nine aripiprazole trials to evaluate strategies for switching patients with schizophrenia to aripiprazole. Paper presented at: 162nd Annual Meeting American Psychiatric Association; May 16-21, 2009; San Francisco, CA.
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31. Kane JM, Barnes TR, Correll CU, et al. Evaluation of akathisia in patients with schizophrenia, schizoaffective disorder, or bipolar I disorder: A post hoc analysis of pooled data from short- and long-term aripiprazole trials. J Psychopharmacol. 2010;24(7):1019-1029.
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33. Kane JM, Osuntokun O, Kryzhanovskaya LA, et al. A 28-week, randomized, double-blind study of olanzapine versus aripiprazole in the treatment of schizophrenia. J Clin Psychiatry. 2009;70(4):572-581.
34. Kane JM, Correll CU, Goff DC, et al. A multicenter, randomized, double-blind, placebo-controlled, 16-week study of adjunctive aripiprazole for schizophrenia or schizoaffective disorder inadequately treated with quetiapine or risperidone monotherapy. J Clin Psychiatry. 2009;70(10):1348-1357.
James J. Gugger, PharmD, BCPP
Dr. Gugger is Assistant Clinical Professor, St. John’s University, College of Pharmacy and Allied Health Professions, Queens, NY
Courtney L. Tam, PharmD
Dr. Tam is Pharmacy Practice Resident, St. John’s University, College of Pharmacy and Allied Health Professions, Queens, NY
Charles R. Ashby, Jr, PhD
Dr. Ashby is Professor, St. John’s University, College of Pharmacy and Allied Health Professions, Queens, NY
Vicki L. Ellingrod, PharmD, BCPP, FCCP
Series Editor
James J. Gugger, PharmD, BCPP
Dr. Gugger is Assistant Clinical Professor, St. John’s University, College of Pharmacy and Allied Health Professions, Queens, NY
Courtney L. Tam, PharmD
Dr. Tam is Pharmacy Practice Resident, St. John’s University, College of Pharmacy and Allied Health Professions, Queens, NY
Charles R. Ashby, Jr, PhD
Dr. Ashby is Professor, St. John’s University, College of Pharmacy and Allied Health Professions, Queens, NY
Vicki L. Ellingrod, PharmD, BCPP, FCCP
Series Editor
James J. Gugger, PharmD, BCPP
Dr. Gugger is Assistant Clinical Professor, St. John’s University, College of Pharmacy and Allied Health Professions, Queens, NY
Courtney L. Tam, PharmD
Dr. Tam is Pharmacy Practice Resident, St. John’s University, College of Pharmacy and Allied Health Professions, Queens, NY
Charles R. Ashby, Jr, PhD
Dr. Ashby is Professor, St. John’s University, College of Pharmacy and Allied Health Professions, Queens, NY
Vicki L. Ellingrod, PharmD, BCPP, FCCP
Series Editor
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• Aripiprazole may interact preferentially with distinct conformations of the D2 receptor, leading to a spectrum of pharmacologic effects, including acting as a full agonist, partial agonist, or antagonist.
• Clinical predictors of aripiprazole-associated worsening of psychosis include low baseline level of psychopathology and previous treatment with high-dose antipsychotics.
• Rapid transition from a medication with significant anticholinergic properties to 1 without these properties may result in symptoms of activation, including restlessness, insomnia, and anxiety, which can be mistaken for worsening psychosis.
• Akathisia, a common adverse effect of aripiprazole, may masquerade as treatment-emergent worsening of psychotic symptoms.
Mr. N, age 29, presents to the emergency department at the urging of his family because of poor self-care, bizarre behavior, and disturbed sleep. He first experienced psychiatric symptoms 10 years ago after his mother died. He became dysphoric and paranoid, displaying bizarre responses and behaviors with poor self-care and a gradual functional decline. He has been taking sertraline, 100 mg/d, for 10 years.
Upon arrival at the hospital’s inpatient unit, Mr. N is unkempt, oddly related, and paranoid. His affect is constricted. Mr. N displays thought blocking and possibly is responding to internal stimuli. Sertraline is continued and haloperidol, 1 mg/d, is initiated. For the next 2 weeks, Mr. N continues to be oddly related, irritable, and paranoid, and experiences disturbed sleep and thought blocking. After an episode of impulsive aggression, the treatment team initiates aripiprazole, which is titrated to 30 mg/d for 1 week. Mr. N’s clinical status worsens; he is menacing toward other patients and his thinking is more disorganized, with loose associations and ideas of reference. He requires 4 injections of IM haloperidol, 5 mg, and several visits to the seclusion room over the next week. Haloperidol is increased to 30 mg/d over the next 10 days, then aripiprazole is discontinued because of a putative drug interaction with haloperidol. Following the medication changes Mr. N demonstrates better behavioral control, but still is grossly psychotic. While awaiting transfer to a state hospital, Mr. N receives a trial of olanzapine, 20 to 40 mg/d, for 2 weeks without significant benefit.
Several clinical trials demonstrate a significant reduction in intensity of psychotic symptoms with aripiprazole, which has a unique mechanism of action.1 However, since its FDA approval in 2002, several case reports have described treatment-emergent psychotic symptoms associated with aripiprazole initiation. Over the past 40 years, reports of worsening psychosis associated with antipsychotics have been limited to patients with schizophrenia who were taking high dosages or who had high plasma concentrations, when anticholinergic delirium may have explained increased psychotic symptoms.2-4
How can a drug effectively treat psychotic symptoms and occasionally worsen them? In this article, we discuss the relevant pharmacology and clinical literature on aripiprazole and try to make sense of this apparent paradox.
Unique pharmacologic profile
Antipsychotics have been reported to be either neutral antagonists or inverse agonists at the D2 receptor, based on in vitro data.5 Aripiprazole and its main metabolite, dehydroaripiprazole, originally were described as partial agonists at D2 dopamine receptors.6,7 However, it appears aripiprazole’s pharmacologic action is better explained by the concept of functional selectivity. Aripiprazole may interact preferentially with distinct conformations of the D2 receptor, leading to a spectrum of pharmacologic effects, including acting as a full agonist, partial agonist, or antagonistic.5
Researchers have hypothesized that the pathophysiology of schizophrenia may, in part, be caused by dysfunction of mesocorticolimbic dopaminergic neurons characterized by an enhanced sensitivity of postsynaptic D2 receptors and increased sensitivity to dopaminergic drugs.8,9 In addition, chronic treatment with a D2 receptor antagonist is associated with increases in postsynaptic dopamine receptor density (ie, an increase in receptor reserve).10,11 Upregulation of D2 receptors may explain several features seen in patients chronically treated with antipsychotics, including tardive dyskinesia12 and rapid psychotic relapse after discontinuing an antipsychotic (supersensitivity psychosis).13 Because chronic antipsychotic treatment leads to high postsynaptic receptor reserve, aripiprazole initiation may produce overactivation of D2 receptors, which might worsen a patient’s condition.14 In vitro data15-18 and clinical observations indicate that aripiprazole has intrinsic efficacy at D2 receptors, as do clinical observations, such as:
- its propensity to reduce serum prolactin19
- a decreased likelihood of producing extrapyramidal side effects despite >80% occupancy of D2 receptors6
- case reports documenting aripiprazole-associated mania,20 improvement of risperidone-associated cognitive impairment,21 and pathologic gambling.22
Emergence or worsening of psychotic symptoms or a marginal antipsychotic effect may occur if aripiprazole is indeed a postsynaptic D2 receptor agonist. An individual patient’s outcome likely would depend on his or her sensitivity to psychosis and concurrent or previous exposure to a D2 receptor antagonist. For example, stimulation of postsynaptic D2 receptors may be further augmented if the dosage of the previous antipsychotic was reduced or withdrawn before initiating aripiprazole because additional receptors would be available for interaction with aripiprazole.
Case reports
A literature review revealed 23 reports of treatment-emergent psychosis associated with aripiprazole initiation (Table). The mean age of the patients was 47 (range: 17 to 69) and 57% were men. Most patients (87%) were diagnosed with a schizophrenia-spectrum illness before aripiprazole initiation. Most (57%) had mild, stable, or no psychotic symptoms before aripiprazole initiation. Most were receiving relatively high doses of antipsychotics (average chlorpromazine equivalents [CPZE]: 648 mg/d) before aripiprazole initiation. This medication was either decreased or discontinued in 70% of patients.
Emergence or worsening of psychotic symptoms included agitation, aggressive behavior, and increased psychomotor activity. However, akathisia evaluation was described in only 2 reports: 1 author identified akathisia symptoms, but attributed them to a concomitant antipsychotic (fluphenazine)23 and the other report specifically excluded the possibility of akathisia.24 Two systematic studies have attempted to establish risk factors for aripiprazole-associated worsening psychosis (Box).14,25
In our literature review, the mean final dose of aripiprazole was 21.5 mg/d (range: 2 to 60 mg/d). In the cases describing subsequent treatment, all but 1 patient were switched to another antipsychotic, including 2 whose psychotic symptoms stabilized with continuation of aripiprazole and addition of a second antipsychotic. Interestingly, in the case reported by Adan-Manes et al,26 initial treatment with aripiprazole monotherapy was efficacious, but a subsequent trial of adjunctive aripiprazole resulted in worsening psychosis.
Table
Case reports: Treatment-emergent psychosis associated with aripiprazole
| Study | Age, sex | Diagnosis | Before aripiprazole initiation | Pre-aripiprazole treatment | Aripiprazole dose | Concomitant psychotropic treatment | Subsequent treatment |
|---|---|---|---|---|---|---|---|
| Chiu et al, 2011a | 39, M | Schizophrenia | Psychiatrically stable, tardive dystonia | Clozapine, 300 mg/d | 10 mg/d | Valproic acid, 1,000 mg/d, clonazepam, 2 mg/d, mephenoxalone, 800 mg/d | Clozapine |
| Ekinci et al, 2010b | 17, M | ADHD | Inattention and impulsive aggression | Tapered and discontinued risperidone, 2.5 mg/d | 5 mg/d | Methylphenidate, 54 mg/d | Risperidone, 2 mg/d, methylphenidate, 36 mg/d |
| Selvaraj et al, 2010c | 49, F | Chronic depression | Depressive symptoms, suicidal ideation | None stated | 2 mg/d | Duloxetine, 80 mg/d, clonazepam, 2 mg/d | Duloxetine, 120 mg/d |
| Adan-Manes et al, 2009d | 23, M | Schizophrenia | No psychotic symptoms | Abrupt decrease of amisulpride dose from 800 mg/d to 400 mg/d | 20 mg/d | Biperiden, 4 mg/d | Amisulpride, 800 mg/d |
| Cho et al, 2009e | 45, F | Schizophrenia | Persistent psychotic symptoms, new onset diabetes with acute ketoacidosis | Haloperidol, 20 mg/d, abrupt clozapine discontinuation | 15 mg/d | Valproic acid, nortriptyline | Molindone, 150 mg/d |
| Ahuja et al, 2007f | 35, F | Schizoaffective disorder | Stable before medication change | Tapered amisulpride, 400 mg/d, over 6 weeks | 15 mg/d | None | Amisulpride, 600 mg/d |
| Lea et al, 2007g | 57, M | Schizophrenia | Persistent psychotic symptoms, treatment resistance, recent recovery from NMS | Discontinued ziprasidone, 200 mg/d | 30 mg/d | Lorazepam, 2 mg/d, amantadine, 100 mg, sertraline, 50 mg/d | Clozapine |
| Lea et al, 2007g | 49, M | Schizoaffective disorder | Delusions, verbal aggression, substance abuse, HCV | Decreased quetiapine dose from 800 mg/d to 400 mg/d | 15 mg/d | Divalproex, 1,000 mg/d, fluvoxamine, 200 mg/d, clonazepam, 2 mg/d | Lithium, quetiapine, 500 mg/d, haloperidol, 2 mg/d |
| Lea et al, 2007g | 60, M | Schizophrenia | Delusions, labile mood, aggression | Risperidone, 3 mg/d, interruption of fluphenazine, 75 mg/d | 20 mg/d | Divalproex, 4,500 mg/d, benztropine, 3 mg/d | Not discussed |
| Raja, 2007h | 30, M | Schizoaffective disorder | Negative symptoms, otherwise stable, recent citalopram discontinuation | Discontinued amisulpride, 800 mg/d over 2 weeks | 30 mg/d | Lithium | Amisulpride, 500 mg/d |
| Raja, 2007h | 69, F | Bipolar disorder | History of multiple relapses; presented with tremor, akathisia, weight gain | Discontinued risperidone, 2 mg/d, over 2 weeks | 15 mg/d | Lithium | Risperidone, 4 mg |
| Raja, 2007h | 59, F | Schizophrenia | Negative symptoms, otherwise stable | Reduced risperidone dosage from 5 mg/d to 4 mg/d | 7.5 mg/d | None | Risperidone, 5 mg/d |
| Thone, 2007i | 31, M | Schizophrenia | Confusion, agitation, delusions worsened with aripiprazole dose increase | None | 60 mg/d | None | Aripiprazole dose reduction to 15 mg/d, olanzapine, 10 mg/d |
| Glick et al, 2006j | 55, F | Schizophrenia | Stable before medication change | Tapered and discontinued thioridazine, 600 mg/d, over 3 months | 30 mg/d | None | Chlorpromazine, 200 mg/d, aripiprazole, 30 mg/d |
| Glick et al, 2006j | 52, M | Schizophrenia | Negative symptoms | Decreased olanzapine dose from 30 mg/d to 20 mg/d | 30 mg/d | None | Olanzapine, 30 mg/d |
| Barnas et al, 2005k | 57, F | Schizoaffective disorder | Stable before medication change | Discontinued perphenazine, 8 mg/d | 30 mg/d | None | Quetiapine, 350 mg/d |
| DeQuardo, 2004l | 54, M | Schizophrenia | History of aggression, residual paranoia, severe EPS | Haloperidol, 200 mg/d | 15 mg/d | Benztropine | Haloperidol |
| DeQuardo, 2004l | 51, M | Schizophrenia | History of aggression, persistent psychotic symptoms, treatment resistance | Olanzapine, 60 mg/d | 10 mg/d | None | Olanzapine |
| Ramaswamy et al, 2004m | 43, F | Schizoaffective disorder | Psychiatrically stable, multiple medication changes, including substituting carbamazepine for valproic acid | Discontinued ziprasidone, 160 mg/d, discontinued quetiapine, 400 mg/d, over 2 weeks | 30 mg/d | Propranolol, 30 mg/d, l-thyroxine, .05 mg/d, carbamazepine, 600 mg/d | Not available |
| Ramaswawamy et al, 2004m | 57, F | Schizoaffective disorder | History of multiple hospitalizations, but stable before medication change | Decreased olanzapine dose from 20 mg/d to 15 mg/d | 30 mg/d | Valproic acid, 2,000 mg/d | Ziprasidone |
| Ramaswawamy et al, 2004m | 67, F | Schizophrenia | Remote hospitalizations, recent worsened psychosis | Decreased ziprasidone dose from 200 mg/d to 160 mg/d 2 months previously | 30 mg/d | Carbamazepine, 200 mg/d | Not discussed |
| Ramaswamy et al, 2004m | 46, M | Schizophrenia | Persistent delusions while receiving risperidone, TD | Risperidone, 3 mg/d | 15 mg/d | Valproic acid, 1,500 mg/d | Risperidone, 3 mg/d |
| Reeves et al, 2004n | 50, M | Schizoaffective disorder | Relatively stable with nonthreatening delusions, hallucinations | Quetiapine, 800 mg/d | 30 mg/d | Divalproex, 2,000 mg/d | Olanzapine, 20 mg/d |
| ADHD: attention-deficit/hyperactivity disorder; EPS: extrapyramidal symptoms; HCV: hepatitis C virus; NMS: neuroleptic malignant syndrome; TD: tardive dyskinesia Source: References a. Chiu YH, Chen CH, Lu ML. Worsening psychosis after adding aripiprazole to clozapine. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35(1):291-292. b. Ekinci O, Sabuncuoglu O. Psychosis associated with switching from risperidone to aripiprazole in an adolescent on methylphenidate treatment. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35(2):648-649. c. Selvaraj V, Ramaswamy S, Sharma A, et al. New-onset psychosis and emergence of suicidal ideation with aripiprazole. Am J Psychiatry. 2010;167(12):1535-1536. d. Adan-Manes J, Garcia-Parajua P. Aripiprazole in combination with other antipsychotic drugs may worsen psychosis. J Clin Pharm Ther. 2009;34(2):245-246. e. Cho DY, Lindenmayer JP. Aripiprazole-induced agitation after clozapine discontinuation: a case report. J Clin Psychiatry. 2009;70(1):141-143. f. Ahuja N, Lloyd AJ. Aripiprazole and worsening of psychosis: a case report. J Clin Psychiatry. 2007;68(5):805-806. g. Lea JW, Stoner SC, Lafollette J. Agitation associated with aripiprazole initiation. Pharmacotherapy. 2007;27(9):1339-1342. h. Raja M. Improvement or worsening of psychotic symptoms after treatment with low doses of aripiprazole. Int J Neuropsychopharmacol. 2007;10(1):107-110. i. Thone J. Worsened agitation and confusion in schizophrenia subsequent to high-dose aripiprazole. J Neuropsychiatry Clin Neurosci. 2007;19(4):481-482. j. Glick ID, Duggal V, Hodulik C. Aripiprazole as a dopamine partial agonist: positive and negative effects. J Clin Psychopharmacol. 2006;26(1):101-103. k. Barnas ME, Hussain N, Petrides G. Treatment-emergent psychosis with aripiprazole. J Clin Psychiatry. 2005;66(10):1339. l. DeQuardo JR. Worsened agitation with aripiprazole: adverse effect of dopamine partial agonism? J Clin Psychiatry. 2004;65(1):132-133. m. Ramaswamy S, Vijay D, William M, et al. Aripiprazole possibly worsens psychosis. Int Clin Psychopharmacol. 2004;19(1):45-48. n. Reeves RR, Mack JE. Worsening schizoaffective disorder with aripiprazole. Am J Psychiatry. 2004;161(7):1308. | |||||||
Takeuchi et al14 aimed to establish predictors of worsening psychosis in a naturalistic setting where patients slowly transitioned to aripiprazole from previous antipsychotic treatment. Patients were required to be on a stable dose of an antipsychotic before participating in the study. Aripiprazole was started at 12 mg/d for 2 weeks with flexible dosing from weeks 2 to 52. Previous antipsychotic therapy was reduced biweekly by 25%. The incidence of worsening psychopathology after aripiprazole initiation was higher in the group of patients who had previously received high-dose antipsychotic therapy (average chlorpromazine equivalents [CPZE]: 727 mg/d) compared with the group on low dosages (average CPZE: 382 mg/d). It is possible that previous high-dose antipsychotic therapy was indicative of more significant baseline psychopathology; however, the worsened group and stabilized group had similar baseline Clinical Global Impressions-Severity scores.
Pae et al25 aimed to find predictors of worsening psychosis with aripiprazole in patients whose previous antipsychotic therapy was immediately discontinued. They found lower baseline disease severity was associated with significant worsening during the first month of aripiprazole treatment.
Other potential explanations
Aripiprazole’s manufacturer reported the incidence of psychosis-related adverse events in an analysis of 9 randomized schizophrenia trials.27 The rates of psychosis-related adverse events ranged from 0.6% to 18%, but there was no apparent relationship to study design or method of transitioning to aripiprazole. Rates of psychosis-related adverse events were similar between aripiprazole and the control group (placebo in 3 studies, another antipsychotic in 2 studies).
Emergence or worsening of psychotic symptoms temporally associated with aripiprazole initiation does not necessarily imply causation. As in Mr. N’s case, it is not always possible to determine whether worsening psychosis is the natural disease course or a treatment effect. In addition, it is not possible to differentiate lack of efficacy from a true propensity for aripiprazole to worsen psychosis.
It also is conceivable discontinuation or dosage reduction of a previous antipsychotic would worsen psychotic symptoms or cause side effects. When significant changes in psychopathology or side effects develop during the transition from 1 antipsychotic to another, it is difficult to determine etiology. Specifically, rapid transition from a medication with significant anticholinergic and antihistaminic properties—such as quetiapine or olanzapine—to 1 without these properties—such as aripiprazole—may result in symptoms of activation, including restlessness, insomnia, and anxiety. Consequently, these symptoms could be mistaken for worsening psychosis.28 Only 1 patient in this series was reported to abruptly discontinue an antipsychotic with significant anticholinergic properties (clozapine) before initiating aripiprazole.24 Studies by Takeuchi et al14 and Pae et al25 did not report the relative baseline use of antipsychotic medication with anticholinergic properties.
In a pooled analysis of treatment-emergent adverse events in 5 randomized clinical trials of patients receiving aripiprazole for acute relapse of schizophrenia, the incidence of akathisia was 10%, although it is not clear if this is a dose-related adverse effect.29 Because akathisia may be confused for worsening psychosis,30 it is possible akathisia was mistakenly identified as worsening psychotic symptoms in Mr. N’s case, as well as several reports from our literature review.
Covert akathisia is unlikely to explain worsening psychopathology observed in all patients in our literature review because confusion of akathisia and worsening psychosis is not a widespread phenomenon. In a post hoc analysis of pooled safety data from aripiprazole trials, Kane et al31 did not find a correlation between presence of akathisia and aripiprazole efficacy as measured by the Positive and Negative Syndrome Scale (PANSS) total, PANSS positive, PANSS negative, Clinical Global Impressions-Severity, Clinical Global Impressions-Improvement, and percentage of responders. Pae et al25 also noted there was no correlation between scores on the Barnes Akathisia Rating Scale and worsening psychopathology in patients switched to aripiprazole.
An antagonist always is an antagonist and clinicians have appreciated this concept since the days of chlorpromazine. The activity of aripiprazole, however, is on a pharmacologic continuum between a neutral antagonist and full agonist and currently there is no way to precisely determine the level of D2 receptor agonist action in a patient.
Although it is interesting to speculate that aripiprazole’s D2 receptor agonist action may contribute to worsening psychosis,32-34 there are other plausible explanations to consider. Rapid transition from a drug with significant anticholinergic properties and aripiprazole-associated akathisia may contribute to worsening psychopathology in patients starting aripiprazole. Because covert side effects may be incorrectly identified as psychotic agitation, we cannot exclude this as a possible etiologic factor in Mr. N’s case as well as the cases in our literature review.
Related Resource
- Abilify [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2011.
Drug Brand Names
- Amantadine • Symmetrel
- Aripiprazole • Abilify
- Benztropine • Cogentin
- Biperiden • Akineton
- Carbamazepine • Tegretol
- Chlorpromazine • Thorazine
- Clonazepam • Klonopin
- Clozapine • Clozaril
- Divalproex • Depakote
- Duloxetine • Cymbalta
- Fluphenazine • Permitil, Prolixin
- Fluvoxamine • Luvox
- Haloperidol • Haldol
- Lithium • Eskalith, Lithobid
- Lorazepam • Ativan
- Nortriptyline • Aventyl, Pamelor
- Methylphenidate • Concerta
- Molindone • Moban
- Olanzapine • Zyprexa
- Perphenazine • Trilafon
- Propranolol • Inderal
- Quetiapine • Seroquel
- Risperidone • Risperdal
- Sertraline • Zoloft
- Thioridazine • Mellaril
- Thyroxine • Synthroid
- Valproic acid • Depakene
- Ziprasidone • Geodon
Disclosure
The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.
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• Aripiprazole may interact preferentially with distinct conformations of the D2 receptor, leading to a spectrum of pharmacologic effects, including acting as a full agonist, partial agonist, or antagonist.
• Clinical predictors of aripiprazole-associated worsening of psychosis include low baseline level of psychopathology and previous treatment with high-dose antipsychotics.
• Rapid transition from a medication with significant anticholinergic properties to 1 without these properties may result in symptoms of activation, including restlessness, insomnia, and anxiety, which can be mistaken for worsening psychosis.
• Akathisia, a common adverse effect of aripiprazole, may masquerade as treatment-emergent worsening of psychotic symptoms.
Mr. N, age 29, presents to the emergency department at the urging of his family because of poor self-care, bizarre behavior, and disturbed sleep. He first experienced psychiatric symptoms 10 years ago after his mother died. He became dysphoric and paranoid, displaying bizarre responses and behaviors with poor self-care and a gradual functional decline. He has been taking sertraline, 100 mg/d, for 10 years.
Upon arrival at the hospital’s inpatient unit, Mr. N is unkempt, oddly related, and paranoid. His affect is constricted. Mr. N displays thought blocking and possibly is responding to internal stimuli. Sertraline is continued and haloperidol, 1 mg/d, is initiated. For the next 2 weeks, Mr. N continues to be oddly related, irritable, and paranoid, and experiences disturbed sleep and thought blocking. After an episode of impulsive aggression, the treatment team initiates aripiprazole, which is titrated to 30 mg/d for 1 week. Mr. N’s clinical status worsens; he is menacing toward other patients and his thinking is more disorganized, with loose associations and ideas of reference. He requires 4 injections of IM haloperidol, 5 mg, and several visits to the seclusion room over the next week. Haloperidol is increased to 30 mg/d over the next 10 days, then aripiprazole is discontinued because of a putative drug interaction with haloperidol. Following the medication changes Mr. N demonstrates better behavioral control, but still is grossly psychotic. While awaiting transfer to a state hospital, Mr. N receives a trial of olanzapine, 20 to 40 mg/d, for 2 weeks without significant benefit.
Several clinical trials demonstrate a significant reduction in intensity of psychotic symptoms with aripiprazole, which has a unique mechanism of action.1 However, since its FDA approval in 2002, several case reports have described treatment-emergent psychotic symptoms associated with aripiprazole initiation. Over the past 40 years, reports of worsening psychosis associated with antipsychotics have been limited to patients with schizophrenia who were taking high dosages or who had high plasma concentrations, when anticholinergic delirium may have explained increased psychotic symptoms.2-4
How can a drug effectively treat psychotic symptoms and occasionally worsen them? In this article, we discuss the relevant pharmacology and clinical literature on aripiprazole and try to make sense of this apparent paradox.
Unique pharmacologic profile
Antipsychotics have been reported to be either neutral antagonists or inverse agonists at the D2 receptor, based on in vitro data.5 Aripiprazole and its main metabolite, dehydroaripiprazole, originally were described as partial agonists at D2 dopamine receptors.6,7 However, it appears aripiprazole’s pharmacologic action is better explained by the concept of functional selectivity. Aripiprazole may interact preferentially with distinct conformations of the D2 receptor, leading to a spectrum of pharmacologic effects, including acting as a full agonist, partial agonist, or antagonistic.5
Researchers have hypothesized that the pathophysiology of schizophrenia may, in part, be caused by dysfunction of mesocorticolimbic dopaminergic neurons characterized by an enhanced sensitivity of postsynaptic D2 receptors and increased sensitivity to dopaminergic drugs.8,9 In addition, chronic treatment with a D2 receptor antagonist is associated with increases in postsynaptic dopamine receptor density (ie, an increase in receptor reserve).10,11 Upregulation of D2 receptors may explain several features seen in patients chronically treated with antipsychotics, including tardive dyskinesia12 and rapid psychotic relapse after discontinuing an antipsychotic (supersensitivity psychosis).13 Because chronic antipsychotic treatment leads to high postsynaptic receptor reserve, aripiprazole initiation may produce overactivation of D2 receptors, which might worsen a patient’s condition.14 In vitro data15-18 and clinical observations indicate that aripiprazole has intrinsic efficacy at D2 receptors, as do clinical observations, such as:
- its propensity to reduce serum prolactin19
- a decreased likelihood of producing extrapyramidal side effects despite >80% occupancy of D2 receptors6
- case reports documenting aripiprazole-associated mania,20 improvement of risperidone-associated cognitive impairment,21 and pathologic gambling.22
Emergence or worsening of psychotic symptoms or a marginal antipsychotic effect may occur if aripiprazole is indeed a postsynaptic D2 receptor agonist. An individual patient’s outcome likely would depend on his or her sensitivity to psychosis and concurrent or previous exposure to a D2 receptor antagonist. For example, stimulation of postsynaptic D2 receptors may be further augmented if the dosage of the previous antipsychotic was reduced or withdrawn before initiating aripiprazole because additional receptors would be available for interaction with aripiprazole.
Case reports
A literature review revealed 23 reports of treatment-emergent psychosis associated with aripiprazole initiation (Table). The mean age of the patients was 47 (range: 17 to 69) and 57% were men. Most patients (87%) were diagnosed with a schizophrenia-spectrum illness before aripiprazole initiation. Most (57%) had mild, stable, or no psychotic symptoms before aripiprazole initiation. Most were receiving relatively high doses of antipsychotics (average chlorpromazine equivalents [CPZE]: 648 mg/d) before aripiprazole initiation. This medication was either decreased or discontinued in 70% of patients.
Emergence or worsening of psychotic symptoms included agitation, aggressive behavior, and increased psychomotor activity. However, akathisia evaluation was described in only 2 reports: 1 author identified akathisia symptoms, but attributed them to a concomitant antipsychotic (fluphenazine)23 and the other report specifically excluded the possibility of akathisia.24 Two systematic studies have attempted to establish risk factors for aripiprazole-associated worsening psychosis (Box).14,25
In our literature review, the mean final dose of aripiprazole was 21.5 mg/d (range: 2 to 60 mg/d). In the cases describing subsequent treatment, all but 1 patient were switched to another antipsychotic, including 2 whose psychotic symptoms stabilized with continuation of aripiprazole and addition of a second antipsychotic. Interestingly, in the case reported by Adan-Manes et al,26 initial treatment with aripiprazole monotherapy was efficacious, but a subsequent trial of adjunctive aripiprazole resulted in worsening psychosis.
Table
Case reports: Treatment-emergent psychosis associated with aripiprazole
| Study | Age, sex | Diagnosis | Before aripiprazole initiation | Pre-aripiprazole treatment | Aripiprazole dose | Concomitant psychotropic treatment | Subsequent treatment |
|---|---|---|---|---|---|---|---|
| Chiu et al, 2011a | 39, M | Schizophrenia | Psychiatrically stable, tardive dystonia | Clozapine, 300 mg/d | 10 mg/d | Valproic acid, 1,000 mg/d, clonazepam, 2 mg/d, mephenoxalone, 800 mg/d | Clozapine |
| Ekinci et al, 2010b | 17, M | ADHD | Inattention and impulsive aggression | Tapered and discontinued risperidone, 2.5 mg/d | 5 mg/d | Methylphenidate, 54 mg/d | Risperidone, 2 mg/d, methylphenidate, 36 mg/d |
| Selvaraj et al, 2010c | 49, F | Chronic depression | Depressive symptoms, suicidal ideation | None stated | 2 mg/d | Duloxetine, 80 mg/d, clonazepam, 2 mg/d | Duloxetine, 120 mg/d |
| Adan-Manes et al, 2009d | 23, M | Schizophrenia | No psychotic symptoms | Abrupt decrease of amisulpride dose from 800 mg/d to 400 mg/d | 20 mg/d | Biperiden, 4 mg/d | Amisulpride, 800 mg/d |
| Cho et al, 2009e | 45, F | Schizophrenia | Persistent psychotic symptoms, new onset diabetes with acute ketoacidosis | Haloperidol, 20 mg/d, abrupt clozapine discontinuation | 15 mg/d | Valproic acid, nortriptyline | Molindone, 150 mg/d |
| Ahuja et al, 2007f | 35, F | Schizoaffective disorder | Stable before medication change | Tapered amisulpride, 400 mg/d, over 6 weeks | 15 mg/d | None | Amisulpride, 600 mg/d |
| Lea et al, 2007g | 57, M | Schizophrenia | Persistent psychotic symptoms, treatment resistance, recent recovery from NMS | Discontinued ziprasidone, 200 mg/d | 30 mg/d | Lorazepam, 2 mg/d, amantadine, 100 mg, sertraline, 50 mg/d | Clozapine |
| Lea et al, 2007g | 49, M | Schizoaffective disorder | Delusions, verbal aggression, substance abuse, HCV | Decreased quetiapine dose from 800 mg/d to 400 mg/d | 15 mg/d | Divalproex, 1,000 mg/d, fluvoxamine, 200 mg/d, clonazepam, 2 mg/d | Lithium, quetiapine, 500 mg/d, haloperidol, 2 mg/d |
| Lea et al, 2007g | 60, M | Schizophrenia | Delusions, labile mood, aggression | Risperidone, 3 mg/d, interruption of fluphenazine, 75 mg/d | 20 mg/d | Divalproex, 4,500 mg/d, benztropine, 3 mg/d | Not discussed |
| Raja, 2007h | 30, M | Schizoaffective disorder | Negative symptoms, otherwise stable, recent citalopram discontinuation | Discontinued amisulpride, 800 mg/d over 2 weeks | 30 mg/d | Lithium | Amisulpride, 500 mg/d |
| Raja, 2007h | 69, F | Bipolar disorder | History of multiple relapses; presented with tremor, akathisia, weight gain | Discontinued risperidone, 2 mg/d, over 2 weeks | 15 mg/d | Lithium | Risperidone, 4 mg |
| Raja, 2007h | 59, F | Schizophrenia | Negative symptoms, otherwise stable | Reduced risperidone dosage from 5 mg/d to 4 mg/d | 7.5 mg/d | None | Risperidone, 5 mg/d |
| Thone, 2007i | 31, M | Schizophrenia | Confusion, agitation, delusions worsened with aripiprazole dose increase | None | 60 mg/d | None | Aripiprazole dose reduction to 15 mg/d, olanzapine, 10 mg/d |
| Glick et al, 2006j | 55, F | Schizophrenia | Stable before medication change | Tapered and discontinued thioridazine, 600 mg/d, over 3 months | 30 mg/d | None | Chlorpromazine, 200 mg/d, aripiprazole, 30 mg/d |
| Glick et al, 2006j | 52, M | Schizophrenia | Negative symptoms | Decreased olanzapine dose from 30 mg/d to 20 mg/d | 30 mg/d | None | Olanzapine, 30 mg/d |
| Barnas et al, 2005k | 57, F | Schizoaffective disorder | Stable before medication change | Discontinued perphenazine, 8 mg/d | 30 mg/d | None | Quetiapine, 350 mg/d |
| DeQuardo, 2004l | 54, M | Schizophrenia | History of aggression, residual paranoia, severe EPS | Haloperidol, 200 mg/d | 15 mg/d | Benztropine | Haloperidol |
| DeQuardo, 2004l | 51, M | Schizophrenia | History of aggression, persistent psychotic symptoms, treatment resistance | Olanzapine, 60 mg/d | 10 mg/d | None | Olanzapine |
| Ramaswamy et al, 2004m | 43, F | Schizoaffective disorder | Psychiatrically stable, multiple medication changes, including substituting carbamazepine for valproic acid | Discontinued ziprasidone, 160 mg/d, discontinued quetiapine, 400 mg/d, over 2 weeks | 30 mg/d | Propranolol, 30 mg/d, l-thyroxine, .05 mg/d, carbamazepine, 600 mg/d | Not available |
| Ramaswawamy et al, 2004m | 57, F | Schizoaffective disorder | History of multiple hospitalizations, but stable before medication change | Decreased olanzapine dose from 20 mg/d to 15 mg/d | 30 mg/d | Valproic acid, 2,000 mg/d | Ziprasidone |
| Ramaswawamy et al, 2004m | 67, F | Schizophrenia | Remote hospitalizations, recent worsened psychosis | Decreased ziprasidone dose from 200 mg/d to 160 mg/d 2 months previously | 30 mg/d | Carbamazepine, 200 mg/d | Not discussed |
| Ramaswamy et al, 2004m | 46, M | Schizophrenia | Persistent delusions while receiving risperidone, TD | Risperidone, 3 mg/d | 15 mg/d | Valproic acid, 1,500 mg/d | Risperidone, 3 mg/d |
| Reeves et al, 2004n | 50, M | Schizoaffective disorder | Relatively stable with nonthreatening delusions, hallucinations | Quetiapine, 800 mg/d | 30 mg/d | Divalproex, 2,000 mg/d | Olanzapine, 20 mg/d |
| ADHD: attention-deficit/hyperactivity disorder; EPS: extrapyramidal symptoms; HCV: hepatitis C virus; NMS: neuroleptic malignant syndrome; TD: tardive dyskinesia Source: References a. Chiu YH, Chen CH, Lu ML. Worsening psychosis after adding aripiprazole to clozapine. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35(1):291-292. b. Ekinci O, Sabuncuoglu O. Psychosis associated with switching from risperidone to aripiprazole in an adolescent on methylphenidate treatment. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35(2):648-649. c. Selvaraj V, Ramaswamy S, Sharma A, et al. New-onset psychosis and emergence of suicidal ideation with aripiprazole. Am J Psychiatry. 2010;167(12):1535-1536. d. Adan-Manes J, Garcia-Parajua P. Aripiprazole in combination with other antipsychotic drugs may worsen psychosis. J Clin Pharm Ther. 2009;34(2):245-246. e. Cho DY, Lindenmayer JP. Aripiprazole-induced agitation after clozapine discontinuation: a case report. J Clin Psychiatry. 2009;70(1):141-143. f. Ahuja N, Lloyd AJ. Aripiprazole and worsening of psychosis: a case report. J Clin Psychiatry. 2007;68(5):805-806. g. Lea JW, Stoner SC, Lafollette J. Agitation associated with aripiprazole initiation. Pharmacotherapy. 2007;27(9):1339-1342. h. Raja M. Improvement or worsening of psychotic symptoms after treatment with low doses of aripiprazole. Int J Neuropsychopharmacol. 2007;10(1):107-110. i. Thone J. Worsened agitation and confusion in schizophrenia subsequent to high-dose aripiprazole. J Neuropsychiatry Clin Neurosci. 2007;19(4):481-482. j. Glick ID, Duggal V, Hodulik C. Aripiprazole as a dopamine partial agonist: positive and negative effects. J Clin Psychopharmacol. 2006;26(1):101-103. k. Barnas ME, Hussain N, Petrides G. Treatment-emergent psychosis with aripiprazole. J Clin Psychiatry. 2005;66(10):1339. l. DeQuardo JR. Worsened agitation with aripiprazole: adverse effect of dopamine partial agonism? J Clin Psychiatry. 2004;65(1):132-133. m. Ramaswamy S, Vijay D, William M, et al. Aripiprazole possibly worsens psychosis. Int Clin Psychopharmacol. 2004;19(1):45-48. n. Reeves RR, Mack JE. Worsening schizoaffective disorder with aripiprazole. Am J Psychiatry. 2004;161(7):1308. | |||||||
Takeuchi et al14 aimed to establish predictors of worsening psychosis in a naturalistic setting where patients slowly transitioned to aripiprazole from previous antipsychotic treatment. Patients were required to be on a stable dose of an antipsychotic before participating in the study. Aripiprazole was started at 12 mg/d for 2 weeks with flexible dosing from weeks 2 to 52. Previous antipsychotic therapy was reduced biweekly by 25%. The incidence of worsening psychopathology after aripiprazole initiation was higher in the group of patients who had previously received high-dose antipsychotic therapy (average chlorpromazine equivalents [CPZE]: 727 mg/d) compared with the group on low dosages (average CPZE: 382 mg/d). It is possible that previous high-dose antipsychotic therapy was indicative of more significant baseline psychopathology; however, the worsened group and stabilized group had similar baseline Clinical Global Impressions-Severity scores.
Pae et al25 aimed to find predictors of worsening psychosis with aripiprazole in patients whose previous antipsychotic therapy was immediately discontinued. They found lower baseline disease severity was associated with significant worsening during the first month of aripiprazole treatment.
Other potential explanations
Aripiprazole’s manufacturer reported the incidence of psychosis-related adverse events in an analysis of 9 randomized schizophrenia trials.27 The rates of psychosis-related adverse events ranged from 0.6% to 18%, but there was no apparent relationship to study design or method of transitioning to aripiprazole. Rates of psychosis-related adverse events were similar between aripiprazole and the control group (placebo in 3 studies, another antipsychotic in 2 studies).
Emergence or worsening of psychotic symptoms temporally associated with aripiprazole initiation does not necessarily imply causation. As in Mr. N’s case, it is not always possible to determine whether worsening psychosis is the natural disease course or a treatment effect. In addition, it is not possible to differentiate lack of efficacy from a true propensity for aripiprazole to worsen psychosis.
It also is conceivable discontinuation or dosage reduction of a previous antipsychotic would worsen psychotic symptoms or cause side effects. When significant changes in psychopathology or side effects develop during the transition from 1 antipsychotic to another, it is difficult to determine etiology. Specifically, rapid transition from a medication with significant anticholinergic and antihistaminic properties—such as quetiapine or olanzapine—to 1 without these properties—such as aripiprazole—may result in symptoms of activation, including restlessness, insomnia, and anxiety. Consequently, these symptoms could be mistaken for worsening psychosis.28 Only 1 patient in this series was reported to abruptly discontinue an antipsychotic with significant anticholinergic properties (clozapine) before initiating aripiprazole.24 Studies by Takeuchi et al14 and Pae et al25 did not report the relative baseline use of antipsychotic medication with anticholinergic properties.
In a pooled analysis of treatment-emergent adverse events in 5 randomized clinical trials of patients receiving aripiprazole for acute relapse of schizophrenia, the incidence of akathisia was 10%, although it is not clear if this is a dose-related adverse effect.29 Because akathisia may be confused for worsening psychosis,30 it is possible akathisia was mistakenly identified as worsening psychotic symptoms in Mr. N’s case, as well as several reports from our literature review.
Covert akathisia is unlikely to explain worsening psychopathology observed in all patients in our literature review because confusion of akathisia and worsening psychosis is not a widespread phenomenon. In a post hoc analysis of pooled safety data from aripiprazole trials, Kane et al31 did not find a correlation between presence of akathisia and aripiprazole efficacy as measured by the Positive and Negative Syndrome Scale (PANSS) total, PANSS positive, PANSS negative, Clinical Global Impressions-Severity, Clinical Global Impressions-Improvement, and percentage of responders. Pae et al25 also noted there was no correlation between scores on the Barnes Akathisia Rating Scale and worsening psychopathology in patients switched to aripiprazole.
An antagonist always is an antagonist and clinicians have appreciated this concept since the days of chlorpromazine. The activity of aripiprazole, however, is on a pharmacologic continuum between a neutral antagonist and full agonist and currently there is no way to precisely determine the level of D2 receptor agonist action in a patient.
Although it is interesting to speculate that aripiprazole’s D2 receptor agonist action may contribute to worsening psychosis,32-34 there are other plausible explanations to consider. Rapid transition from a drug with significant anticholinergic properties and aripiprazole-associated akathisia may contribute to worsening psychopathology in patients starting aripiprazole. Because covert side effects may be incorrectly identified as psychotic agitation, we cannot exclude this as a possible etiologic factor in Mr. N’s case as well as the cases in our literature review.
Related Resource
- Abilify [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2011.
Drug Brand Names
- Amantadine • Symmetrel
- Aripiprazole • Abilify
- Benztropine • Cogentin
- Biperiden • Akineton
- Carbamazepine • Tegretol
- Chlorpromazine • Thorazine
- Clonazepam • Klonopin
- Clozapine • Clozaril
- Divalproex • Depakote
- Duloxetine • Cymbalta
- Fluphenazine • Permitil, Prolixin
- Fluvoxamine • Luvox
- Haloperidol • Haldol
- Lithium • Eskalith, Lithobid
- Lorazepam • Ativan
- Nortriptyline • Aventyl, Pamelor
- Methylphenidate • Concerta
- Molindone • Moban
- Olanzapine • Zyprexa
- Perphenazine • Trilafon
- Propranolol • Inderal
- Quetiapine • Seroquel
- Risperidone • Risperdal
- Sertraline • Zoloft
- Thioridazine • Mellaril
- Thyroxine • Synthroid
- Valproic acid • Depakene
- Ziprasidone • Geodon
Disclosure
The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.
1. Citrome L. A review of aripiprazole in the treatment of patients with schizophrenia or bipolar I disorder. Neuropsychiatr Dis Treat. 2006;2(4):427-443.
2. Chong SA, Tan CH, Lee HS. Worsening of psychosis with clozapine and selective serotonin reuptake inhibitor combination: two case reports. J Clin Psychopharmacol. 1997;17(1):68-69.
3. Bowers MB Jr, Swigar ME. Psychotic patients who become worse on neuroleptics. J Clin Psychopharmacol. 1988;8(6):417-421.
4. Tornatore FL, Lee D, Sramek JJ. Psychotic exacerbation with haloperidol. Drug Intell Clin Pharm. 1981;15(3):209-213.
5. Beaulieu JM, Gainetdinov RR. The physiology signaling, and pharmacology of dopamine receptors. Pharmacol Rev. 2011;63(1):182-217.
6. Grunder G, Carlsson A, Wong DF. Mechanism of new antipsychotic medications: occupancy is not just antagonism. Arch Gen Psychiatry. 2003;60(10):974-977.
7. Wood MD, Scott C, Clarke K, et al. Aripiprazole and its human metabolite are partial agonists at the human dopamine D2 receptor, but the rodent metabolite displays antagonist properties. Eur J Pharmacol. 2006;546(1-3):88-94.
8. Seeman P, Weinshenker D, Quirion R, et al. Dopamine supersensitivity correlates with D2High states, implying many paths to psychosis. Proc Natl Acad Sci U S A. 2005;102(9):3513-3518.
9. Seeman P, Ko F, Jack E, et al. Consistent with dopamine supersensitivity, RGS9 expression is diminished in the amphetamine-treated animal model of schizophrenia and in postmortem schizophrenia brain. Synapse. 2007;61(5):303-309.
10. Burt DR, Creese I, Snyder SH. Antischizophrenic drugs: chronic treatment elevates dopamine receptor binding in brain. Science. 1977;196(4287):326-328.
11. Silvestri S, Seeman MV, Negrete JC, et al. Increased dopamine D2 receptor binding after long-term treatment with antipsychotics in humans: a clinical PET study. Psychopharmacology (Berl). 2000;152(2):174-180.
12. Sayers AC, Bürki HR, Ruch W, et al. Neuroleptic-induced hypersensitivity of striatal dopamine receptors in the rat as a model of tardive dyskinesias. Effects of clozapine, haloperidol, loxapine and chlorpromazine. Psychopharmacologia. 1975;41(2):97-104.
13. Moncrieff J. Does antipsychotic withdrawal provoke psychosis? Review of the literature on rapid onset psychosis (supersensitivity psychosis) and withdrawal-related relapse. Acta Psychiatr Scand. 2006;114(1):3-13.
14. Takeuchi H, Uchida H, Suzuki T, et al. Predictors of clinical worsening after a switch to aripiprazole in patients with schizophrenia: a 1-year naturalistic follow-up study. J Clin Psychopharmacol. 2009;29(4):394-395.
15. Shapiro DA, Renock S, Arrington E, et al. Aripiprazole, a novel atypical antipsychotic drug with a unique and robust pharmacology. Neuropsychopharmacology. 2003;28(8):1400-1411.
16. Urban JD, Vargas GA, von Zastrow M, et al. Aripiprazole has functionally selective actions at dopamine D2 receptor-mediated signaling pathways. Neuropsychopharmacology. 2007;32(1):67-77.
17. Klewe IV, Nielsen SM, Tarpo L, et al. Recruitment of beta-arrestin2 to the dopamine D2 receptor: Insights into anti-psychotic and anti-parkinsonian drug receptor signaling. Neuropharmacology. 2008;54(8):1215-1222.
18. Masri B, Salahpour A, Didriksen M, et al. Antagonism of dopamine D2 receptor/beta-arrestin 2 interaction is a common property of clinically effective antipsychotics. Proc Natl Acad Sci U S A. 2008;105(36):13656-13661.
19. Shim JC, Shin JG, Kelly DL, et al. Adjunctive treatment with a dopamine partial agonist, aripiprazole, for antipsychotic-induced hyperprolactinemia: a placebo-controlled trial. Am J Psychiatry. 2007;164(9):1404-1410.
20. Padala PR, Wengel SP, Petty F. Manic episode during treatment with aripiprazole. Am J Psychiatry. 2007;164(1):172-173.
21. Hu CH, Pai N, Huang XF, et al. Potential control of risperidone-related cognitive deficits by adjunctive aripiprazole treatment. J Clin Psychopharmacol. 2011;31(1):135-136;author reply 136–137.
22. Cohen J, Magalon D, Boyer L, et al. Aripiprazole-induced pathological gambling: a report of 3 cases. Curr Drug Saf. 2011;6(1):51-53.
23. Lea JW, Stoner SC, Lafollette J. Agitation associated with aripiprazole initiation. Pharmacotherapy. 2007;27(9):1339-1342.
24. Cho DY, Lindenmayer JP. Aripiprazole-induced agitation after clozapine discontinuation: a case report. J Clin Psychiatry. 2009;70(1):141-143.
25. Pae CU, Chiesa A, Mandelli L, et al. Predictors of early worsening after switch to aripiprazole: a randomized, controlled, open-label study. Clin Drug Investig. 2010;30(3):187-193.
26. Adan-Manes J, Garcia-Parajua P. Aripiprazole in combination with other antipsychotic drugs may worsen psychosis. J Clin Pharm Ther. 2009;34(2):245-246.
27. Cognata-Smith C, Baker RA, Pikalov A, et al. Analysis of nine aripiprazole trials to evaluate strategies for switching patients with schizophrenia to aripiprazole. Paper presented at: 162nd Annual Meeting American Psychiatric Association; May 16-21, 2009; San Francisco, CA.
28. Lieberman J. Cholinergic rebound in neuroleptic withdrawal syndromes. Psychosomatics. 1981;22(3):253-254.
29. Marder SR, McQuade RD, Stock E, et al. Aripiprazole in the treatment of schizophrenia: Safety and tolerability in short-term, placebo-controlled trials. Schizophr Res. 2003;61(2-3):123-136.
30. Kane JM, Fleischhacker WW, Hansen L, et al. Akathisia: an updated review focusing on second-generation antipsychotics. J Clin Psychiatry. 2009;70(5):627-643.
31. Kane JM, Barnes TR, Correll CU, et al. Evaluation of akathisia in patients with schizophrenia, schizoaffective disorder, or bipolar I disorder: A post hoc analysis of pooled data from short- and long-term aripiprazole trials. J Psychopharmacol. 2010;24(7):1019-1029.
32. Fleischhacker WW, McQuade RD, Marcus RN, et al. A double-blind, randomized comparative study of aripiprazole and olanzapine in patients with schizophrenia. Biol Psychiatry. 2009;65(6):510-517.
33. Kane JM, Osuntokun O, Kryzhanovskaya LA, et al. A 28-week, randomized, double-blind study of olanzapine versus aripiprazole in the treatment of schizophrenia. J Clin Psychiatry. 2009;70(4):572-581.
34. Kane JM, Correll CU, Goff DC, et al. A multicenter, randomized, double-blind, placebo-controlled, 16-week study of adjunctive aripiprazole for schizophrenia or schizoaffective disorder inadequately treated with quetiapine or risperidone monotherapy. J Clin Psychiatry. 2009;70(10):1348-1357.
1. Citrome L. A review of aripiprazole in the treatment of patients with schizophrenia or bipolar I disorder. Neuropsychiatr Dis Treat. 2006;2(4):427-443.
2. Chong SA, Tan CH, Lee HS. Worsening of psychosis with clozapine and selective serotonin reuptake inhibitor combination: two case reports. J Clin Psychopharmacol. 1997;17(1):68-69.
3. Bowers MB Jr, Swigar ME. Psychotic patients who become worse on neuroleptics. J Clin Psychopharmacol. 1988;8(6):417-421.
4. Tornatore FL, Lee D, Sramek JJ. Psychotic exacerbation with haloperidol. Drug Intell Clin Pharm. 1981;15(3):209-213.
5. Beaulieu JM, Gainetdinov RR. The physiology signaling, and pharmacology of dopamine receptors. Pharmacol Rev. 2011;63(1):182-217.
6. Grunder G, Carlsson A, Wong DF. Mechanism of new antipsychotic medications: occupancy is not just antagonism. Arch Gen Psychiatry. 2003;60(10):974-977.
7. Wood MD, Scott C, Clarke K, et al. Aripiprazole and its human metabolite are partial agonists at the human dopamine D2 receptor, but the rodent metabolite displays antagonist properties. Eur J Pharmacol. 2006;546(1-3):88-94.
8. Seeman P, Weinshenker D, Quirion R, et al. Dopamine supersensitivity correlates with D2High states, implying many paths to psychosis. Proc Natl Acad Sci U S A. 2005;102(9):3513-3518.
9. Seeman P, Ko F, Jack E, et al. Consistent with dopamine supersensitivity, RGS9 expression is diminished in the amphetamine-treated animal model of schizophrenia and in postmortem schizophrenia brain. Synapse. 2007;61(5):303-309.
10. Burt DR, Creese I, Snyder SH. Antischizophrenic drugs: chronic treatment elevates dopamine receptor binding in brain. Science. 1977;196(4287):326-328.
11. Silvestri S, Seeman MV, Negrete JC, et al. Increased dopamine D2 receptor binding after long-term treatment with antipsychotics in humans: a clinical PET study. Psychopharmacology (Berl). 2000;152(2):174-180.
12. Sayers AC, Bürki HR, Ruch W, et al. Neuroleptic-induced hypersensitivity of striatal dopamine receptors in the rat as a model of tardive dyskinesias. Effects of clozapine, haloperidol, loxapine and chlorpromazine. Psychopharmacologia. 1975;41(2):97-104.
13. Moncrieff J. Does antipsychotic withdrawal provoke psychosis? Review of the literature on rapid onset psychosis (supersensitivity psychosis) and withdrawal-related relapse. Acta Psychiatr Scand. 2006;114(1):3-13.
14. Takeuchi H, Uchida H, Suzuki T, et al. Predictors of clinical worsening after a switch to aripiprazole in patients with schizophrenia: a 1-year naturalistic follow-up study. J Clin Psychopharmacol. 2009;29(4):394-395.
15. Shapiro DA, Renock S, Arrington E, et al. Aripiprazole, a novel atypical antipsychotic drug with a unique and robust pharmacology. Neuropsychopharmacology. 2003;28(8):1400-1411.
16. Urban JD, Vargas GA, von Zastrow M, et al. Aripiprazole has functionally selective actions at dopamine D2 receptor-mediated signaling pathways. Neuropsychopharmacology. 2007;32(1):67-77.
17. Klewe IV, Nielsen SM, Tarpo L, et al. Recruitment of beta-arrestin2 to the dopamine D2 receptor: Insights into anti-psychotic and anti-parkinsonian drug receptor signaling. Neuropharmacology. 2008;54(8):1215-1222.
18. Masri B, Salahpour A, Didriksen M, et al. Antagonism of dopamine D2 receptor/beta-arrestin 2 interaction is a common property of clinically effective antipsychotics. Proc Natl Acad Sci U S A. 2008;105(36):13656-13661.
19. Shim JC, Shin JG, Kelly DL, et al. Adjunctive treatment with a dopamine partial agonist, aripiprazole, for antipsychotic-induced hyperprolactinemia: a placebo-controlled trial. Am J Psychiatry. 2007;164(9):1404-1410.
20. Padala PR, Wengel SP, Petty F. Manic episode during treatment with aripiprazole. Am J Psychiatry. 2007;164(1):172-173.
21. Hu CH, Pai N, Huang XF, et al. Potential control of risperidone-related cognitive deficits by adjunctive aripiprazole treatment. J Clin Psychopharmacol. 2011;31(1):135-136;author reply 136–137.
22. Cohen J, Magalon D, Boyer L, et al. Aripiprazole-induced pathological gambling: a report of 3 cases. Curr Drug Saf. 2011;6(1):51-53.
23. Lea JW, Stoner SC, Lafollette J. Agitation associated with aripiprazole initiation. Pharmacotherapy. 2007;27(9):1339-1342.
24. Cho DY, Lindenmayer JP. Aripiprazole-induced agitation after clozapine discontinuation: a case report. J Clin Psychiatry. 2009;70(1):141-143.
25. Pae CU, Chiesa A, Mandelli L, et al. Predictors of early worsening after switch to aripiprazole: a randomized, controlled, open-label study. Clin Drug Investig. 2010;30(3):187-193.
26. Adan-Manes J, Garcia-Parajua P. Aripiprazole in combination with other antipsychotic drugs may worsen psychosis. J Clin Pharm Ther. 2009;34(2):245-246.
27. Cognata-Smith C, Baker RA, Pikalov A, et al. Analysis of nine aripiprazole trials to evaluate strategies for switching patients with schizophrenia to aripiprazole. Paper presented at: 162nd Annual Meeting American Psychiatric Association; May 16-21, 2009; San Francisco, CA.
28. Lieberman J. Cholinergic rebound in neuroleptic withdrawal syndromes. Psychosomatics. 1981;22(3):253-254.
29. Marder SR, McQuade RD, Stock E, et al. Aripiprazole in the treatment of schizophrenia: Safety and tolerability in short-term, placebo-controlled trials. Schizophr Res. 2003;61(2-3):123-136.
30. Kane JM, Fleischhacker WW, Hansen L, et al. Akathisia: an updated review focusing on second-generation antipsychotics. J Clin Psychiatry. 2009;70(5):627-643.
31. Kane JM, Barnes TR, Correll CU, et al. Evaluation of akathisia in patients with schizophrenia, schizoaffective disorder, or bipolar I disorder: A post hoc analysis of pooled data from short- and long-term aripiprazole trials. J Psychopharmacol. 2010;24(7):1019-1029.
32. Fleischhacker WW, McQuade RD, Marcus RN, et al. A double-blind, randomized comparative study of aripiprazole and olanzapine in patients with schizophrenia. Biol Psychiatry. 2009;65(6):510-517.
33. Kane JM, Osuntokun O, Kryzhanovskaya LA, et al. A 28-week, randomized, double-blind study of olanzapine versus aripiprazole in the treatment of schizophrenia. J Clin Psychiatry. 2009;70(4):572-581.
34. Kane JM, Correll CU, Goff DC, et al. A multicenter, randomized, double-blind, placebo-controlled, 16-week study of adjunctive aripiprazole for schizophrenia or schizoaffective disorder inadequately treated with quetiapine or risperidone monotherapy. J Clin Psychiatry. 2009;70(10):1348-1357.