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Is there a link between and treatment-emergent psychosis?

James J. Gugger, PharmD, BCPP, Courtney L. Tam, PharmD, and Charles R. Ashby, Jr, PhD

r. N, age 29, presents to the emergency Several clinical trials demonstrate a sig- Mdepartment at the urging of his fam- nificant reduction in intensity of psychotic ily because of poor self-care, bizarre behav- symptoms with aripiprazole, which has a ior, and disturbed sleep. He first experienced unique .1 However, since psychiatric symptoms 10 years ago after his its FDA approval in 2002, several case reports mother died. He became dysphoric and para- have described treatment-emergent psychot- noid, displaying bizarre responses and behav- ic symptoms associated with aripiprazole Vicki L. Ellingrod, iors with poor self-care and a gradual func- initiation. Over the past 40 years, reports of PharmD, BCPP, FCCP tional decline. He has been taking , worsening psychosis associated with anti- Series Editor 100 mg/d, for 10 years. psychotics have been limited to patients with Upon arrival at the hospital’s inpatient unit, who were taking high dos- Mr. N is unkempt, oddly related, and paranoid. ages or who had high plasma concentrations, His affect is constricted. Mr. N displays thought when delirium may have ex- blocking and possibly is responding to internal plained increased psychotic symptoms.2-4 stimuli. Sertraline is continued and , How can a drug effectively treat psy- 1 mg/d, is initiated. For the next 2 weeks, Mr. chotic symptoms and occasionally worsen N continues to be oddly related, irritable, and paranoid, and experiences disturbed sleep and Practice Points thought blocking. After an episode of impul- • Aripiprazole may interact preferentially sive aggression, the treatment team initiates with distinct conformations of the aripiprazole, which is titrated to 30 mg/d for 1 D2 receptor, leading to a spectrum of week. Mr. N’s clinical status worsens; he is men- pharmacologic effects, including acting as acing toward other patients and his thinking is a full , , or antagonist. more disorganized, with loose associations and • Clinical predictors of aripiprazole- ideas of reference. He requires 4 injections of IM associated worsening of psychosis include haloperidol, 5 mg, and several visits to the seclu- low baseline level of psychopathology sion room over the next week. Haloperidol is in- and previous treatment with high-dose creased to 30 mg/d over the next 10 days, then . aripiprazole is discontinued because of a puta- • Rapid transition from a with tive drug interaction with haloperidol. Following significant anticholinergic properties to the medication changes Mr. N demonstrates 1 without these properties may result better behavioral control, but still is grossly psy- in symptoms of activation, including restlessness, , and , which chotic. While awaiting transfer to a state hospi- can be mistaken for worsening psychosis. tal, Mr. N receives a trial of , 20 to 40 mg/d, for 2 weeks without significant benefit. • , a common adverse effect of aripiprazole, may masquerade as Dr. Gugger is Assistant Clinical Professor, Dr. Tam is Pharmacy treatment-emergent worsening of Practice Resident, and Dr. Ashby is Professor, St. John’s University, psychotic symptoms. Current Psychiatry College of Pharmacy and Allied Health Professions, Queens, NY. Vol. 10, No. 10 53 Savvy Psychopharmacology

them? In this article, we discuss the rele- -associated cognitive impair- vant pharmacology and clinical literature ment,21 and pathologic gambling.22 on aripiprazole and try to make sense of Emergence or worsening of psychotic this apparent paradox. symptoms or a marginal ef- fect may occur if aripiprazole is indeed a postsynaptic D2 receptor agonist. An in- Unique pharmacologic profile dividual patient’s outcome likely would Antipsychotics have been reported to be depend on his or her sensitivity to psycho- either neutral antagonists or inverse ago- sis and concurrent or previous exposure nists at the D2 receptor, based on in vitro to a D2 receptor antagonist. For example, data.5 Aripiprazole and its main metabo- stimulation of postsynaptic D2 receptors lite, dehydroaripiprazole, originally were may be further augmented if the dosage of described as partial at D2 dopa- the previous antipsychotic was reduced or mine receptors.6,7 However, it appears ari­ withdrawn before initiating aripiprazole piprazole’s pharmacologic action is better because additional receptors would be explained by the concept of functional se- available for interaction with aripiprazole. Clinical Point lectivity. Aripiprazole may interact prefer- Aripiprazole entially with distinct conformations of the D2 receptor, leading to a spectrum of phar- Case reports initiation macologic effects, including acting as a full A literature review revealed 23 reports of may produce agonist, partial agonist, or antagonistic.5 treatment-emergent psychosis associated overactivation of D2 Researchers have hypothesized that the with aripiprazole initiation (Table, page receptors, which pathophysiology of schizophrenia may, in 56-57). The mean age of the patients was might worsen a part, be caused by dysfunction of meso- 47 (range: 17 to 69) and 57% were men. corticolimbic neurons char- Most patients (87%) were diagnosed with patient’s condition acterized by an enhanced sensitivity of a schizophrenia-spectrum illness before ar- postsynaptic D2 receptors and increased ipiprazole initiation. Most (57%) had mild, sensitivity to dopaminergic drugs.8,9 In ad- stable, or no psychotic symptoms before dition, chronic treatment with a D2 recep- aripiprazole initiation. Most were receiv- tor antagonist is associated with increases ing relatively high doses of antipsychot- in postsynaptic receptor den- ics (average equivalents sity (ie, an increase in receptor reserve).10,11 [CPZE]: 648 mg/d) before aripiprazole Upregulation of D2 receptors may explain initiation. This medication was either de- several features seen in patients chronical- creased or discontinued in 70% of patients. ly treated with antipsychotics, including Emergence or worsening of psychotic tardive dyskinesia12 and rapid psychotic symptoms included agitation, aggres- relapse after discontinuing an antipsychot- sive behavior, and increased psychomo- ic (supersensitivity psychosis).13 Because tor activity. However, akathisia evalua- chronic antipsychotic treatment leads to tion was described in only 2 reports: 1 high postsynaptic receptor reserve, aripip- author identified akathisia symptoms, razole initiation may produce overactiva- but attributed them to a concomitant an- tion of D2 receptors, which might worsen tipsychotic ()23 and the other a patient’s condition.14 In vitro data15-18 and report specifically excluded the possibil- clinical observations indicate that aripipra- ity of akathisia.24 Two systematic studies zole has intrinsic efficacy at D2 receptors, have attempted to establish risk factors for as do clinical observations, such as: aripiprazole-associated worsening psy- • its propensity to reduce serum chosis (Box).14,25 prolactin19 In our literature review, the mean fi- • a decreased likelihood of producing nal dose of aripiprazole was 21.5 mg/d extrapyramidal side effects despite >80% (range: 2 to 60 mg/d). In the cases describ- occupancy of D2 receptors6 ing subsequent treatment, all but 1 patient • case reports documenting aripipra- were switched to another antipsychotic, Current Psychiatry 54 October 2011 zole-associated ,20 improvement of including 2 whose psychotic symptoms Savvy Psychopharmacology

Box Clinical predictors of aripiprazole-associated psychotic symptoms

akeuchi et al14 aimed to establish predictors [CPZE]: 727 mg/d) compared with the group on Tof worsening psychosis in a naturalistic low dosages (average CPZE: 382 mg/d). It is setting where patients slowly transitioned possible that previous high-dose antipsychotic to aripiprazole from previous antipsychotic therapy was indicative of more significant treatment. Patients were required to be on baseline psychopathology; however, the a stable dose of an antipsychotic before worsened group and stabilized group had similar participating in the study. Aripiprazole baseline Clinical Global Impressions-Severity was started at 12 mg/d for 2 weeks with scores. flexible dosing from weeks 2 to 52. Previous Pae et al25 aimed to find predictors of antipsychotic therapy was reduced biweekly worsening psychosis with aripiprazole in patients by 25%. The incidence of worsening whose previous antipsychotic therapy was psychopathology after aripiprazole initiation immediately discontinued. They found lower was higher in the group of patients who had baseline disease severity was associated with previously received high-dose antipsychotic significant worsening during the first month of therapy (average chlorpromazine equivalents aripiprazole treatment. Clinical Point Emergence of or cause side effects. When significant stabilized with continuation of aripipra- psychotic symptoms zole and addition of a second antipsychot- changes in psychopathology or side effects ic. Interestingly, in the case reported by develop during the transition from 1 anti­ temporally Adan-Manes et al,26 initial treatment with psychotic to another, it is difficult to de- associated with aripiprazole monotherapy was efficacious, termine etiology. Specifically, rapid tran- aripiprazole but a subsequent trial of adjunctive aripip- sition from a medication with significant initiation does not razole resulted in worsening psychosis. anticholinergic and antihistaminic prop- erties—such as or olanzap- imply causation ine—to 1 without these properties—such Other potential explanations as aripiprazole—may result in symptoms Aripiprazole’s manufacturer reported of activation, including restlessness, in- the incidence of psychosis-related ad- somnia, and anxiety. Consequently, these verse events in an analysis of 9 random- symptoms could be mistaken for worsen- ized schizophrenia trials.27 The rates of ing psychosis.28 Only 1 patient in this series psychosis-related adverse events ranged was reported to abruptly discontinue an from 0.6% to 18%, but there was no appar- antipsychotic with significant anticholin- ent relationship to study design or method ergic properties () before initiat- of transitioning to aripiprazole. Rates of ing aripiprazole.24 Studies by Takeuchi et psychosis-related adverse events were al14 and Pae et al25 did not report the rela- similar between aripiprazole and the con- tive baseline use of antipsychotic medica- trol group (placebo in 3 studies, another tion with anticholinergic properties. antipsychotic in 2 studies). In a pooled analysis of treatment- Emergence or worsening of psychotic emergent adverse events in 5 randomized symptoms temporally associated with ar- clinical trials of patients receiving aripipra- ipiprazole initiation does not necessarily zole for acute relapse of schizophrenia, the imply causation. As in Mr. N’s case, it is incidence of akathisia was 10%, although it not always possible to determine whether is not clear if this is a dose-related adverse worsening psychosis is the natural disease effect.29 Because akathisia may be confused course or a treatment effect. In addition, it for worsening psychosis,30 it is possible is not possible to differentiate lack of effi- akathisia was mistakenly identified as cacy from a true propensity for aripipra- worsening psychotic symptoms in Mr. N’s zole to worsen psychosis. case, as well as several reports from our lit- It also is conceivable discontinuation or erature review. dosage reduction of a previous antipsy- Covert akathisia is unlikely to explain Current Psychiatry chotic would worsen psychotic symptoms worsening psychopathology observed in Vol. 10, No. 10 55 continued on page 58 Savvy Psychopharmacology

Table Case reports: Treatment-emergent psychosis associated with aripiprazole

Age, Aripiprazole Concomitant Study sex Diagnosis Before aripiprazole initiation Pre-aripiprazole treatment dose 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, Clozapine , 2 mg/d, mephenoxalone, 800 mg/d Ekinci et al, 2010b 17, M ADHD Inattention and impulsive aggression Tapered and discontinued 5 mg/d , 54 mg/d Risperidone, 2 mg/d, risperidone, 2.5 mg/d methylphenidate, 36 mg/d Selvaraj et al, 49, F Chronic Depressive symptoms, suicidal ideation None stated 2 mg/d , 80 mg/d, Duloxetine, 120 mg/d 2010c clonazepam, 2 mg/d Adan-Manes et al, 23, M Schizophrenia No psychotic symptoms Abrupt decrease of dose 20 mg/d Biperiden, 4 mg/d Amisulpride, 800 mg/d 2009d from 800 mg/d to 400 mg/d Cho et al, 2009e 45, F Schizophrenia Persistent psychotic symptoms, new onset diabetes with Haloperidol, 20 mg/d, abrupt 15 mg/d Valproic acid, , 150 mg/d acute ketoacidosis clozapine discontinuation Ahuja et al, 2007f 35, F Schizoaffective Stable before medication change Tapered amisulpride, 400 mg/d, 15 mg/d None Amisulpride, 600 mg/d Clinical Point disorder over 6 weeks Lea et al, 2007g 57, M Schizophrenia Persistent psychotic symptoms, treatment resistance, recent Discontinued , 200 mg/d 30 mg/d , 2 mg/d, Clozapine It is not possible to recovery from NMS , 100 mg, differentiate lack sertraline, 50 mg/d Lea et al, 2007g 49, M Schizoaffective Delusions, verbal aggression, substance abuse, HCV Decreased quetiapine dose from 15 mg/d Divalproex, 1,000 mg/d, , quetiapine, 500 of efficacy from disorder 800 mg/d to 400 mg/d , 200 mg/d, mg/d, haloperidol, 2 mg/d a true propensity clonazepam, 2 mg/d Lea et al, 2007g 60, M Schizophrenia Delusions, labile mood, aggression Risperidone, 3 mg/d, interruption of 20 mg/d Divalproex, 4,500 mg/d, Not discussed for aripiprazole to fluphenazine, 75 mg/d benztropine, 3 mg/d worsen psychotic Raja, 2007h 30, M Schizoaffective Negative symptoms, otherwise stable, recent Discontinued amisulpride, 800 mg/d 30 mg/d Lithium Amisulpride, 500 mg/d symptoms disorder discontinuation over 2 weeks Raja, 2007h 69, F History of multiple relapses; presented with tremor, akathisia, Discontinued risperidone, 2 mg/d, 15 mg/d Lithium Risperidone, 4 mg weight gain over 2 weeks Raja, 2007h 59, F Schizophrenia Negative symptoms, otherwise stable Reduced risperidone dosage from 7.5 mg/d None Risperidone, 5 mg/d 5 mg/d to 4 mg/d Thone, 2007i 31, M Schizophrenia Confusion, agitation, delusions worsened with aripiprazole None 60 mg/d None Aripiprazole dose reduction dose increase to 15 mg/d, olanzapine, 10 mg/d Glick et al, 2006 j 55, F Schizophrenia Stable before medication change Tapered and discontinued 30 mg/d None Chlorpromazine, 200 mg/d, , 600 mg/d, over 3 months aripiprazole, 30 mg/d Glick et al, 2006 j 52, M Schizophrenia Negative symptoms Decreased olanzapine dose from 30 mg/d None Olanzapine, 30 mg/d 30 mg/d to 20 mg/d Barnas et al, 2005k 57, F Schizoaffective Stable before medication change Discontinued , 8 mg/d 30 mg/d None Quetiapine, 350 mg/d disorder 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, Olanzapine, 60 mg/d 10 mg/d None Olanzapine treatment resistance Ramaswamy 43, F Schizoaffective Psychiatrically stable, multiple medication changes, including Discontinued ziprasidone, 160 mg/d, 30 mg/d , 30 mg/d, Not available et al, 2004m disorder substituting for valproic acid discontinued quetiapine, 400 mg/d, l-thyroxine, .05 mg/d, over 2 weeks carbamazepine, 600 mg/d Ramaswawamy 57, F Schizoaffective History of multiple hospitalizations, but stable before Decreased olanzapine dose from 30 mg/d Valproic acid, 2,000 mg/d Ziprasidone et al, 2004m disorder medication change 20 mg/d to 15 mg/d Ramaswawamy 67, F Schizophrenia Remote hospitalizations, recent worsened psychosis Decreased ziprasidone dose from 30 mg/d Carbamazepine, 200 mg/d Not discussed et al, 2004m 200 mg/d to 160 mg/d 2 months previously Ramaswamy 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 et al, 2004m Reeves et al, 50, M Schizoaffective Relatively stable with nonthreatening delusions, hallucinations Quetiapine, 800 mg/d 30 mg/d Divalproex, 2,000 mg/d Olanzapine, 20 mg/d 2004n disorder ADHD: attention-deficit/hyperactivity disorder; EPS: ; HCV: hepatitis C virus; NMS: neuroleptic malignant syndrome; TD: Current Psychiatry 56 October 2011 Source: For reference citations, see this article at CurrentPsychiatry.com Savvy Psychopharmacology

Case reports: Treatment-emergent psychosis associated with aripiprazole

Age, Aripiprazole Concomitant Study sex Diagnosis Before aripiprazole initiation Pre-aripiprazole treatment dose 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, Clozapine clonazepam, 2 mg/d, mephenoxalone, 800 mg/d Ekinci et al, 2010b 17, M ADHD Inattention and impulsive aggression Tapered and discontinued 5 mg/d Methylphenidate, 54 mg/d Risperidone, 2 mg/d, risperidone, 2.5 mg/d methylphenidate, 36 mg/d Selvaraj et al, 49, F Chronic Depressive symptoms, suicidal ideation None stated 2 mg/d Duloxetine, 80 mg/d, Duloxetine, 120 mg/d 2010c depression clonazepam, 2 mg/d Adan-Manes et al, 23, M Schizophrenia No psychotic symptoms Abrupt decrease of amisulpride dose 20 mg/d Biperiden, 4 mg/d Amisulpride, 800 mg/d 2009d from 800 mg/d to 400 mg/d Cho et al, 2009e 45, F Schizophrenia Persistent psychotic symptoms, new onset diabetes with Haloperidol, 20 mg/d, abrupt 15 mg/d Valproic acid, nortriptyline Molindone, 150 mg/d acute ketoacidosis clozapine discontinuation Ahuja et al, 2007f 35, F Schizoaffective Stable before medication change Tapered amisulpride, 400 mg/d, 15 mg/d None Amisulpride, 600 mg/d disorder over 6 weeks Clinical Point Lea et al, 2007g 57, M Schizophrenia Persistent psychotic symptoms, treatment resistance, recent Discontinued ziprasidone, 200 mg/d 30 mg/d Lorazepam, 2 mg/d, Clozapine recovery from NMS amantadine, 100 mg, Covert akathisia sertraline, 50 mg/d may not explain Lea et al, 2007g 49, M Schizoaffective Delusions, verbal aggression, substance abuse, HCV Decreased quetiapine dose from 15 mg/d Divalproex, 1,000 mg/d, Lithium, quetiapine, 500 disorder 800 mg/d to 400 mg/d fluvoxamine, 200 mg/d, mg/d, haloperidol, 2 mg/d worsening clonazepam, 2 mg/d psychopathology Lea et al, 2007g 60, M Schizophrenia Delusions, labile mood, aggression Risperidone, 3 mg/d, interruption of 20 mg/d Divalproex, 4,500 mg/d, Not discussed fluphenazine, 75 mg/d benztropine, 3 mg/d observed in all Raja, 2007h 30, M Schizoaffective Negative symptoms, otherwise stable, recent citalopram Discontinued amisulpride, 800 mg/d 30 mg/d Lithium Amisulpride, 500 mg/d patients in our disorder discontinuation over 2 weeks literature review Raja, 2007h 69, F Bipolar disorder History of multiple relapses; presented with tremor, akathisia, Discontinued risperidone, 2 mg/d, 15 mg/d Lithium Risperidone, 4 mg weight gain over 2 weeks Raja, 2007h 59, F Schizophrenia Negative symptoms, otherwise stable Reduced risperidone dosage from 7.5 mg/d None Risperidone, 5 mg/d 5 mg/d to 4 mg/d Thone, 2007i 31, M Schizophrenia Confusion, agitation, delusions worsened with aripiprazole None 60 mg/d None Aripiprazole dose reduction dose increase to 15 mg/d, olanzapine, 10 mg/d Glick et al, 2006 j 55, F Schizophrenia Stable before medication change Tapered and discontinued 30 mg/d None Chlorpromazine, 200 mg/d, thioridazine, 600 mg/d, over 3 months aripiprazole, 30 mg/d Glick et al, 2006 j 52, M Schizophrenia Negative symptoms Decreased olanzapine dose from 30 mg/d None Olanzapine, 30 mg/d 30 mg/d to 20 mg/d Barnas et al, 2005k 57, F Schizoaffective Stable before medication change Discontinued perphenazine, 8 mg/d 30 mg/d None Quetiapine, 350 mg/d disorder 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, Olanzapine, 60 mg/d 10 mg/d None Olanzapine treatment resistance Ramaswamy 43, F Schizoaffective Psychiatrically stable, multiple medication changes, including Discontinued ziprasidone, 160 mg/d, 30 mg/d Propranolol, 30 mg/d, Not available et al, 2004m disorder substituting carbamazepine for valproic acid discontinued quetiapine, 400 mg/d, l-thyroxine, .05 mg/d, over 2 weeks carbamazepine, 600 mg/d Ramaswawamy 57, F Schizoaffective History of multiple hospitalizations, but stable before Decreased olanzapine dose from 30 mg/d Valproic acid, 2,000 mg/d Ziprasidone et al, 2004m disorder medication change 20 mg/d to 15 mg/d Ramaswawamy 67, F Schizophrenia Remote hospitalizations, recent worsened psychosis Decreased ziprasidone dose from 30 mg/d Carbamazepine, 200 mg/d Not discussed et al, 2004m 200 mg/d to 160 mg/d 2 months previously Ramaswamy 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 et al, 2004m Reeves et al, 50, M Schizoaffective Relatively stable with nonthreatening delusions, hallucinations Quetiapine, 800 mg/d 30 mg/d Divalproex, 2,000 mg/d Olanzapine, 20 mg/d 2004n disorder ADHD: attention-deficit/hyperactivity disorder; EPS: extrapyramidal symptoms; HCV: hepatitis C virus; NMS: neuroleptic malignant syndrome; TD: tardive dyskinesia Current Psychiatry Source: For reference citations, see this article at CurrentPsychiatry.com Vol. 10, No. 10 57 Savvy Psychopharmacology

continued from page 55 erties and aripiprazole-associated akathisia Related Resource may contribute to worsening psychopa- • Abilify [package insert]. Princeton, NJ: Bristol-Myers Squibb; thology in patients starting aripiprazole. 2011. Because covert side effects may be incor- Drug Brand Names rectly identified as psychotic agitation, we Amantadine • Symmetrel Lorazepam • Ativan Aripiprazole • Abilify Nortriptyline • Aventyl, cannot exclude this as a possible etiologic Benztropine • Cogentin Pamelor factor in Mr. N’s case as well as the cases in Biperiden • Akineton Methylphenidate • Concerta our literature review. Carbamazepine • Tegretol Molindone • Moban Chlorpromazine • Thorazine Olanzapine • Zyprexa Clonazepam • Klonopin Perphenazine • Trilafon References Clozapine • Clozaril Propranolol • Inderal 1. Citrome L. A review of aripiprazole in the treatment of patients Divalproex • Depakote Quetiapine • Seroquel with schizophrenia or . Neuropsychiatr Dis Duloxetine • Cymbalta Risperidone • Risperdal Treat. 2006;2(4):427-443. Fluphenazine • Permitil, Sertraline • Zoloft 2. Chong SA, Tan CH, Lee HS. Worsening of psychosis Prolixin Thioridazine • Mellaril with clozapine and selective reuptake inhibitor Fluvoxamine • Luvox Thyroxine • Synthroid combination: two case reports. J Clin Psychopharmacol. 1997; Haloperidol • Haldol Valproic acid • Depakene 17(1):68-69. Lithium • Eskalith, Lithobid Ziprasidone • Geodon 3. Bowers MB Jr, Swigar ME. Psychotic patients who become worse on neuroleptics. J Clin Psychopharmacol. 1988;8(6): Clinical Point Disclosure 417-421. The authors report no financial relationship with any company 4. Tornatore FL, Lee D, Sramek JJ. Psychotic exacerbation with Aripiprazole’s whose products are mentioned in this article or with manufactur- haloperidol. Drug Intell Clin Pharm. 1981;15(3):209-213. ers of competing products. 5. Beaulieu JM, Gainetdinov RR. The physiology, signaling, and pharmacology of dopamine receptors. Pharmacol Rev. activity is on a 2011;63(1):182-217. pharmacologic 6. Grunder G, Carlsson A, Wong DF. Mechanism of new antipsychotic : occupancy is not just antagonism. continuum between Arch Gen Psychiatry. 2003;60(10):974-977. 7. Wood MD, Scott C, Clarke K, et al. Aripiprazole and its human a neutral antagonist all patients in our literature review because metabolite are partial agonists at the human dopamine confusion of akathisia and worsening psy- D2 receptor, but the rodent metabolite displays antagonist and full agonist properties. Eur J Pharmacol. 2006;546(1-3):88-94. chosis is not a widespread phenomenon. In a 8. Seeman P, Weinshenker D, Quirion R, et al. Dopamine post hoc analysis of pooled safety data from supersensitivity correlates with D2High states, implying many paths to psychosis. Proc Natl Acad Sci U S A. 2005; 31 aripiprazole trials, Kane et al did not find 102(9):3513-3518. a correlation between presence of akathisia 9. Seeman P, Ko F, Jack E, et al. Consistent with dopamine supersensitivity, RGS9 expression is diminished in the and aripiprazole efficacy as measured by -treated animal model of schizophrenia and in the Positive and Negative Syndrome Scale postmortem schizophrenia brain. Synapse. 2007;61(5):303-309. 10. Burt DR, Creese I, Snyder SH. Antischizophrenic drugs: (PANSS) total, PANSS positive, PANSS neg- chronic treatment elevates binding in ative, Clinical Global Impressions-Severity, brain. Science. 1977;196(4287):326-328. 11. Silvestri S, Seeman MV, Negrete JC, et al. Increased Clinical Global Impressions-Improvement, dopamine D2 receptor binding after long-term treatment and percentage of responders. Pae et al25 with antipsychotics in humans: a clinical PET study. Psychopharmacology (Berl). 2000;152(2):174-180. also noted there was no correlation between 12. Sayers AC, Bürki HR, Ruch W, et al. Neuroleptic-induced scores on the Barnes Akathisia Rating Scale hypersensitivity of striatal dopamine receptors in the rat as a model of tardive dyskinesias. Effects of clozapine, haloperidol, and worsening psychopathology in pa- and chlorpromazine. Psychopharmacologia. 1975; tients switched to aripiprazole. 41(2):97-104. 13. Moncrieff J. Does antipsychotic withdrawal provoke An antagonist always is an antagonist psychosis? Review of the literature on rapid onset psychosis (supersensitivity psychosis) and withdrawal-related relapse. and clinicians have appreciated this con- Acta Psychiatr Scand. 2006;114(1):3-13. cept since the days of chlorpromazine. 14. Takeuchi H, Uchida H, Suzuki T, et al. 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Recruitment of beta- arrestin2 to the dopamine D2 receptor: Insights into anti- tion may contribute to worsening psycho- psychotic and anti-parkinsonian drug receptor signaling. sis,32-34 there are other plausible explana- Neuropharmacology. 2008;54(8):1215-1222. 18. Masri B, Salahpour A, Didriksen M, et al. Antagonism tions to consider. Rapid transition from a Current Psychiatry of dopamine D2 receptor/beta-arrestin 2 interaction is a 58 October 2011 drug with significant anticholinergic prop- common property of clinically effective antipsychotics. Proc Savvy Psychopharmacology

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