Is there a link between aripiprazole and treatment-emergent psychosis?

Current Psychiatry. 2011 October;10(10):53-60

October 1, 2011|Psychiatry

Clinical Point

Emergence of psychotic symptoms temporally associated with aripiprazole initiation does not imply causation

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, 2011^a	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, 2010^b	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, 2010^c	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, 2009^d	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, 2009^e	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, 2007^f	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, 2007^g	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, 2007^g	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, 2007^g	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, 2007^h	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, 2007^h	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, 2007^h	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, 2006^j	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, 2006^j	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, 2005^k	57, F	Schizoaffective disorder	Stable before medication change	Discontinued perphenazine, 8 mg/d	30 mg/d	None	Quetiapine, 350 mg/d
DeQuardo, 2004^l	54, M	Schizophrenia	History of aggression, residual paranoia, severe EPS	Haloperidol, 200 mg/d	15 mg/d	Benztropine	Haloperidol
DeQuardo, 2004^l	51, M	Schizophrenia	History of aggression, persistent psychotic symptoms, treatment resistance	Olanzapine, 60 mg/d	10 mg/d	None	Olanzapine
Ramaswamy et al, 2004^m	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, 2004^m	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, 2004^m	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, 2004^m	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.

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