To Name :
To Email :
From Name :
From Email :
Comments :

Savvy Psychopharmacology


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

Vol. 10, No. 10 / October 2011

Discuss this article at www.facebook.com/CurrentPsychiatry

Practice Points

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.


Clinical predictors of aripiprazole-associated psychotic symptoms

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.

Continued...
Did you miss this content?
How to prevent misuse of psychotropics among college students