Abstract
The abrupt appearance of clozapine discontinuation symptoms represents a particularly unique situation that has not been characterized in a double- blind, placebo-controlled trial. A randomized, double-blind comparison of placebo (N = 53) and olanzapine 10 mg (N = 53) for 3 to 5 days following the abrupt discontinuation of clozapine (≤ 300 mg/day) was carried out. Subjects were assessed with the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impression Scale of Severity, the Montgomery-Asberg Depression Rating Scale (MADRS), and the Mini-Mental State Evaluation. Subsequently both groups received open-label olanzapine (10-25 mg/day) for an additional 9 weeks. Statistically significantly more placebo-treated (24.5%) than olanzapine-treated (7.5%) patients experienced clozapine discontinuation symptoms (p = 0.017). Core symptoms included delusions, hallucinations, hostility, and paranoid reaction and translated into a significantly higher worsening from baseline on the PANSS total, PANSS General Psychopathology subscale, and MADRS among subjects randomly assigned to receive placebo. After open-label treatment with olanzapine for 9 weeks, both groups were clinically stable, suggesting that the discontinuation symptoms were transient. However, subjects who had been randomly assigned to the 3- to 5- day placebo discontinuation segment achieved somewhat less global clinical improvement. Although a pharmacologic interpretation is speculative, evidence of a clozapine discontinuation syndrome was apparent. In most cases, the direct substitution of a pharmacologically similar agent (olanzapine) prevented the syndrome. Clozapine discontinuation or noncompliance should be considered in the differential assessment of an acutely emergent psychosis. The possibility that subjects who experience a clozapine discontinuation syndrome may take longer or are less likely to clinically restabilize warrants further investigation.
| Original language | English |
|---|---|
| Pages (from-to) | 435-443 |
| Number of pages | 9 |
| Journal | Journal of Clinical Psychopharmacology |
| Volume | 19 |
| Issue number | 5 |
| DOIs | |
| State | Published - Oct 1 1999 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Psychiatry and Mental health
- Pharmacology (medical)
- Pharmacology, Toxicology and Pharmaceutics(all)
Cite this
Controlled, double-blind investigation of the clozapine discontinuation symptoms with conversion to either olanzapine or placebo. / Tollefson, Gary D.; Dellva, Mary Anne; Mattler, Carole A.; Kane, John M.; Wirshing, Donna A.; Kinon, Bruce J.; Ames, Donna; Cohn, Cal K.; Daniel, David G.; Clark, Scott C.; Horne, Robert L.; Levine, Robert; Miller, Marvin; Nemeroff, Charles; Reinstein, Michael R.; Smith, Thomas E.
In: Journal of Clinical Psychopharmacology, Vol. 19, No. 5, 01.10.1999, p. 435-443.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Controlled, double-blind investigation of the clozapine discontinuation symptoms with conversion to either olanzapine or placebo
AU - Tollefson, Gary D.
AU - Dellva, Mary Anne
AU - Mattler, Carole A.
AU - Kane, John M.
AU - Wirshing, Donna A.
AU - Kinon, Bruce J.
AU - Ames, Donna
AU - Cohn, Cal K.
AU - Daniel, David G.
AU - Clark, Scott C.
AU - Horne, Robert L.
AU - Levine, Robert
AU - Miller, Marvin
AU - Nemeroff, Charles
AU - Reinstein, Michael R.
AU - Smith, Thomas E.
PY - 1999/10/1
Y1 - 1999/10/1
N2 - The abrupt appearance of clozapine discontinuation symptoms represents a particularly unique situation that has not been characterized in a double- blind, placebo-controlled trial. A randomized, double-blind comparison of placebo (N = 53) and olanzapine 10 mg (N = 53) for 3 to 5 days following the abrupt discontinuation of clozapine (≤ 300 mg/day) was carried out. Subjects were assessed with the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impression Scale of Severity, the Montgomery-Asberg Depression Rating Scale (MADRS), and the Mini-Mental State Evaluation. Subsequently both groups received open-label olanzapine (10-25 mg/day) for an additional 9 weeks. Statistically significantly more placebo-treated (24.5%) than olanzapine-treated (7.5%) patients experienced clozapine discontinuation symptoms (p = 0.017). Core symptoms included delusions, hallucinations, hostility, and paranoid reaction and translated into a significantly higher worsening from baseline on the PANSS total, PANSS General Psychopathology subscale, and MADRS among subjects randomly assigned to receive placebo. After open-label treatment with olanzapine for 9 weeks, both groups were clinically stable, suggesting that the discontinuation symptoms were transient. However, subjects who had been randomly assigned to the 3- to 5- day placebo discontinuation segment achieved somewhat less global clinical improvement. Although a pharmacologic interpretation is speculative, evidence of a clozapine discontinuation syndrome was apparent. In most cases, the direct substitution of a pharmacologically similar agent (olanzapine) prevented the syndrome. Clozapine discontinuation or noncompliance should be considered in the differential assessment of an acutely emergent psychosis. The possibility that subjects who experience a clozapine discontinuation syndrome may take longer or are less likely to clinically restabilize warrants further investigation.
AB - The abrupt appearance of clozapine discontinuation symptoms represents a particularly unique situation that has not been characterized in a double- blind, placebo-controlled trial. A randomized, double-blind comparison of placebo (N = 53) and olanzapine 10 mg (N = 53) for 3 to 5 days following the abrupt discontinuation of clozapine (≤ 300 mg/day) was carried out. Subjects were assessed with the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impression Scale of Severity, the Montgomery-Asberg Depression Rating Scale (MADRS), and the Mini-Mental State Evaluation. Subsequently both groups received open-label olanzapine (10-25 mg/day) for an additional 9 weeks. Statistically significantly more placebo-treated (24.5%) than olanzapine-treated (7.5%) patients experienced clozapine discontinuation symptoms (p = 0.017). Core symptoms included delusions, hallucinations, hostility, and paranoid reaction and translated into a significantly higher worsening from baseline on the PANSS total, PANSS General Psychopathology subscale, and MADRS among subjects randomly assigned to receive placebo. After open-label treatment with olanzapine for 9 weeks, both groups were clinically stable, suggesting that the discontinuation symptoms were transient. However, subjects who had been randomly assigned to the 3- to 5- day placebo discontinuation segment achieved somewhat less global clinical improvement. Although a pharmacologic interpretation is speculative, evidence of a clozapine discontinuation syndrome was apparent. In most cases, the direct substitution of a pharmacologically similar agent (olanzapine) prevented the syndrome. Clozapine discontinuation or noncompliance should be considered in the differential assessment of an acutely emergent psychosis. The possibility that subjects who experience a clozapine discontinuation syndrome may take longer or are less likely to clinically restabilize warrants further investigation.
UR - http://www.scopus.com/inward/record.url?scp=0032842391&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0032842391&partnerID=8YFLogxK
U2 - 10.1097/00004714-199910000-00007
DO - 10.1097/00004714-199910000-00007
M3 - Article
VL - 19
SP - 435
EP - 443
JO - Journal of Clinical Psychopharmacology
JF - Journal of Clinical Psychopharmacology
SN - 0271-0749
IS - 5
ER -