Safety of ipsapirone treatment compared with lorazepam: discontinuation effects.
OBJECTIVE
To determine discontinuation effects of ipsapirone, a novel azapirone and partial 5-HTIA agonist that has anxiolytic effects clinically and has not caused dependence or withdrawal symptoms in animals, and to compare these effects with those of the benzodiazepine lorazepam, owing to concern about dependence or withdrawal symptoms following use of these drugs.


METHODS
Prospective, randomized, double-blind, placebo-controlled trial.


METHODS
Outpatient and inpatient treatment.


METHODS
Sixty-five healthy male volunteers who had experience with sedative-hypnotics or anxiolytics and did not meet DSM-III-R criteria for abuse or dependence.


METHODS
Participants were randomized to receive ipsapirone 15 mg per day (n = 17), ipsapirone 22.5 mg per day (n = 16), lorazepam 3 mg per day (n = 16), or placebo (n = 16) as outpatients for 36 days (treatment) followed by single-blind placebo as inpatients for 3 days and as outpatients for 6 days (withdrawal).


METHODS
Hamilton Anxiety Rating Scale (HAM-A), Hamilton Depression Scale (HAM-D), Spielberger State Anxiety Scale, Sleep Quality Questionnaire, General Symptom Checklist, self-rated intoxication, Clinical Institute Withdrawal Assessment--Benzodiazepines (CIWA-Benzo), psychomotor testing and urine drug screen.


RESULTS
Only 45 subjects completed the study; discontinuation rates did not significantly differ among treatment groups. At day 39, fewer and less severe symptoms (e.g., insomnia and fatigue) were found on the CIWA-Benzo scale after treatment with ipsapirone or placebo than after treatment with lorazepam (p < 0.05). Subjects reported longer sleep latency and poorer sleep quality after receiving lorazepam than after receiving ipsapirone or placebo. Scores on the HAM-D, Spielberger State Anxiety and HAM-A scales did not change from baseline.


CONCLUSIONS
Withdrawal symptoms were detected after discontinuation of therapeutic doses of lorazepam. Significantly fewer symptoms were observed after withdrawal from anxiolytic doses of ipsapirone.
Busto
U E
UE
University of Toronto, Sunnybrook Health Science Centre, Psychopharmacology Research Program, North York, ON. ubusto@arf.org
Naranjo
C A
CA
Bremner
K E
KE
Peachey
J E
JE
Bologa
M
M
D000328:Adult; D014151:Anti-Anxiety Agents / Q000009:adverse effects* / Q000627:therapeutic use; D004311:Double-Blind Method; D006801:Humans; D008140:Lorazepam / Q000009:adverse effects* / Q000627:therapeutic use; D008297:Male; D011446:Prospective Studies; D011743:Pyrimidines / Q000009:adverse effects* / Q000627:therapeutic use; D013375:Substance Withdrawal Syndrome / Q000523:psychology*
D014151:Anti-Anxiety Agents; D011743:Pyrimidines; C043077:ipsapirone; D008140:Lorazepam