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Quetiapine, a second-generation antipsychotic agent, has shown efficacy and safety in the treatment of patients with schizophrenia experiencing an acute exacerbation of their illness (1,2). Further, pharmacokinetic data suggest quetiapine has a plasma half-life of nearly 6 hours, which is slightly increased with multiple dosing. Thus, in spite of an elimination half-life that averages 6 hours (range 5.8 to 6.8 hours [3]), quetiapine has been shown to be therapeutically equivalent when dosed at either 2 or 3 times daily (4). Among the key pharmacokinetic variables that guide dosing of a drug are its plasma elimination half-life, the presence or absence of active metabolites, whether the drug exhibits linear pharmacokinetics, and the time taken to achieve steady-state levels of the drug. Therefore, quetiapine, which exhibits a linear pharmacokinetic profile over its therapeutic dosage range (150 to 750 mg daily), reaches steady-state plasma levels in 2 days. To maintain these steady-state plasma levels, it would follow that quetiapine needs to be administered 2 or 3 times daily. However, there is no known one-to-one correspondence between plasma levels of a drug and its levels in the central nervous system (CNS) or, for that matter, between plasma levels and drug-receptor occupancy. Further, recent positron emission tomography (PET) data suggest that neither high rates of dopamine (D2) receptor occupancy nor sustained blockade of these receptors is necessary for antipsychotic efficacy (5). These new PET data have led to the concepts of tight (for example, haloperidol) vs loose (for example, clozapine and quetiapine) D2 receptor binding and sustained (for example, haloperidol) vs transient and surmountable (for example, clozapine and quetiapine) blockade of D2 receptors to explain the rationale for the efficacy of the second-generation antipsychotic agents, such as clozapine and quetiapine. One corollary to this hypothesis would be to test the dosing frequency of drugs such as clozapine and quetiapine at less frequent intervals than predicted by their pharmacologic half-lives. If quetiapine, with a relatively short elimination half-life, could be dosed as a single daily dose, it might result in a greater adherence to treatment by patients in the long term. The objective of this study was to evaluate whether quetiapine fumarate dosed once a day was therapeutically equivalent to twice-daily dosing in subjects who had reached a stable therapeutic dose. MethodsStudy Design Baseline screening assessments, medical history, and psychiatric history were recorded after written informed consent was obtained from participants. Patients with a diagnosis of schizoaffective disorder were permitted to continue mood stabilizers, either lithium, valproate, or antidepressant medications, unchanged in dosage throughout the double-blind phase. Lorazepam (up to 4 mg daily) was permitted for episodic agitation on an as-needed basis, as were hypnotic agents for insomnia. After the withdrawal of routine antiparkinsonian agents (1 week following the last dosage of the previous antipsychotic agent), their use was permitted only for newly emergent extrapyramidal symptoms (EPS) based on clinical judgement and after ratings for EPS were completed. Patient Population Pregnant or lactating women or women of reproductive age without adequate contraception were excluded, as were subjects considered to be actively suicidal or homicidal. Those receiving injectable long-acting neuroleptic agents (or within one injection cycle of study entry) were excluded.
Assessments Statistical Analysis A 1-way repeated-measures analysis of variance (ANOVA) was used to examine the relation between successive PANSS total scores and subscale scores at weeks 0, 4, 8, and 12 in the study sample as a whole, as well as in the groups assigned to once- or twice-daily administration separately. If the main effect was significant, post hoc pairwise differences between visit mean changes were examined using Bonferroni’s adjustment for multiple comparisons. Subsequently, a mixed-model, repeated-measures ANOVA with the clinical measures (PANSS total or subscale scores) as the within- subject factor and the randomly assigned (once or twice daily) as the between-subject factor was performed to examine the interaction between the 2 factors. PANSS subscale change scores, as well as change scores for the HDRS, CGI severity, and GAF, were analyzed for the entire group using the last observation carried forward (LOCF) method rather than a “completers” analysis. However, it is pertinent to note that only 2 of 21 randomized subjects dropped out at the penultimate visit of the double-blind phase of the study and that their data were carried forward to the last visit. ResultsBaseline Characteristics Patient Disposition Efficacy Analyses Figure 1 Patients (n = 10) who were assigned to once-daily quetiapine administration at week 4 Figure 2 Patients (n = 11) who were assigned to twice-daily quetiapine administration at week 4
Secondary Analyses The total and subscale change scores of PANSS and other efficacy assessments are presented in Tables 2 and 3 for the entire group as well as for those assigned to either once- or twice-daily dosing with quetiapine. The LOCF analyses for the entire group showed a significant improvement in the PANSS total and subscale scores, as well as the CGI severity scores, HDRS scores, and GAF scores.
Safety Analyses The final switchover point occurred at the end of the double-blind phase. Among 15 responding subjects, 14 voluntarily chose the once-daily open treatment, and 1 subject chose the twice-daily regimen. None of the 15 subjects worsened at this switch point. Additional Safety Evaluation. Adverse effects elicited or reported during the titration and stable administration periods and the double-blind period, at a rate of at least 1 subject (that is, 5%) or more were somnolence (5/21, 24%), headache (4/21, 19%), dizziness (3/21, 14%), constipation (1/21, 5%), urinary incontinence (1/21, 5%), and insomnia (1/21, 5%). These adverse effects were noted mostly in the first 4 to 8 weeks of treatment and were of mild-to-moderate severity. These events did not lead to withdrawal from the study, either resolved in time or with symptomatic treatment, and did not reoccur during the crossover phase, except for somnolence in 1 subject, intermittent headache in 1 subject, and constipation in 1 subject. Symptomatic postural hypotension was noted in 4 subjects (19%) during the titration phase of the study. For 2 of these 4 subjects, symptomatic postural hypotension recurred in the crossover phase of the blinded study. These events occurred during the crossover from once- to twice-daily dosing or vice versa. Five subjects experienced akathisia at baseline, and 5 subjects evidenced EPS at baseline. Four subjects had TD (using research diagnostic criteria for TD [13]) at baseline. Akathisia resolved in all subjects by 4 weeks of quetiapine treatment, and EPS resolved in 6 to 8 weeks of treatment. No new cases of akathisia or other EPS were noted in the double-blind phases of the study. Two of the 4 subjects with TD showed evidence of worsening (withdrawal dyskinesia) for up to 6 weeks but, by the end of the double-blind study, had AIMS scores lower than at baseline. The other 2 subjects with TD at baseline showed a gradual and steady improvement of the scores during the study. All 4 subjects had lower AIMS scores by the end of the study (data not shown). The mean body weight for the entire group was 87.7 kg (SD 17.3) at baseline and increased by a mean of 3.1 kg (SD 4.8) toward the end of the double-blind phase of the study (t = 2.9, df 20, P = 0.008). The weight gain was noted over a duration of 11 to 12 weeks of quetiapine treatment, and it is important to note all subjects with schizoaffective disorders were also receiving either mood stabilizers or antidepressant medicines as concomitant therapy. During the double-blind phase, there were 27 doses of lorazepam dispensed for episodic agitation or anxiety. These differences were not statistically significant between the once- and twice-daily administration groups and occurred mainly in the first 4 weeks of treatment. There were only 3 instances of anticholinergic use for EPS: once in a person receiving once-daily treatment and twice in subjects assigned to twice-daily dosing. These instances occurred shortly after the switch from the previous antipsychotic agents during the open-titration and stabilization phase. Adherence to Medications
DiscussionThese preliminary data suggest that most subjects who had reached a therapeutic dose of quetiapine fumarate (400 or 600 mg daily) on a twice-daily administration schedule were switched to the once-daily regimen without significant difficulty. A minority (3/21, 15%) of subjects worsened clinically during the switch, and so it would be clinically prudent to closely monitor subjects for the first 2 to 4 weeks after the switch to once-daily administration. Just prior to the initiation of the double-blind randomization phase, all subjects were receiving the twice-daily regimen, and 10 subjects were randomized to the once-daily regimen, whereas 11 continued on the twice-daily regimen. None of the 10 subjects randomized to once-daily administration at this point experienced any worsening of symptoms. Four weeks later, at the crossover point, 2 subjects showed evidence of worsening after initial improvement. Based on the initial improvement and worsening shortly following the switch, it is likely that the temporal deterioration in these 2 subjects was associated with the change in the administration schedule. One occurred in a subject crossing from the once- to twice-daily regimen (1/10, 10%) and another in a subject moving from twice- to once-daily regimen (1/11, 9%). Is it possible that supersensitivity has a role to play in these patients (14)? Subjects who had received the previous oral antipsychotic agents for 6 to 8 weeks were tapered off their medicines in 1 to 2 weeks, and the phenomena were noted within 6 weeks (15). Thus, in sensitive individuals who have shown the need for escalating dosages of first-generation neuroleptic agents in the recent past, have increased psychotic symptoms just before a depot neuroleptic injection, or have symptoms of schizophrenia that are different from earlier exacerbations on medication withdrawal may show deterioration in the switching over to quetiapine. In such individuals a slower switch may be appropriate. Interestingly, and similar to the experience of Chouinard and others (16) in treating supersensitivity psychoses, we too noted significant improvement with clozapine in 2 patients who worsened at the switchover point in the current study. A third subject assigned to the twice-daily regimen, who had not improved through the first 4 weeks of double-blind treatment, worsened at the crossover but stayed the course through the next 4 weeks. While it is possible that the worsening of symptoms in this last subject was caused by the switch in administration schedule, it is also likely that this clinical worsening was associated with the natural course of the illness. In some subjects, attention to sedation and postural hypotension is clinically advisable both during the titration phase and following the switch to once-daily administration, especially among those subjects who are treated with antihypertensive medicines or have diabetes mellitus. However, in most subjects, administration of the entire dose of quetiapine at bedtime may help minimize the risk of orthostatic hypotension and sedation, as patients are more likely to be recumbent during the peak plasma concentrations of the drug. It is possible that some subjects switching from agents with an anticholinergic profile to quetiapine could experience a cholinergic rebound, and perhaps a longer taper of the anticholinergic agent may be useful (17). In some subjects, worsening of the preexisting TD may have been caused by unmasking of TD occurring during a switch from a potent and tight D2 receptor antagonist (first-generation agents) to quetiapine. However, with the passage of time, the symptoms of TD diminished considerably on continued quetiapine treatment to less than the prequetiapine baseline. Emerging data sets from PET studies in patients with schizophrenia have begun to suggest that D2 receptor occupancy by antipsychotic agents need not be very high; further, the question has arisen whether such receptor blockade needs to be sustained continuously (18). The PET data from patients treated with depot haloperidol injections or oral clozapine and quetiapine-treated subjects would argue otherwise (19,20). A second set of questions raised by recent PET data regarding quetiapine specifically suggest that transiently high D2 occupancy rates (58% to 64%) may be adequate for treatment response (18). More recently, the same group also noted that first-episode patients who responded to quetiapine did not differ from those who did not, simply based on peak and trough D2 receptor occupancy rates (20). A third line of support for once-daily administration of relatively short half-life drugs comes from clinical experience in clozapine clinics. Subsets of subjects who have achieved steady-state drug levels and reached stable target dosages of clozapine (that is, those who are not also encumbered by dosage-related adverse effects: seizures, sedation, and postural hypotension) can be switched to a once-daily dosing regimen (mainly for patient convenience and to increase adherence to treatment) without loss of antipsychotic efficacy. These converging lines of evidence provide the rationale for the dosing of quetiapine fumarate as a single daily dose in subjects who have already reached a stable target dosage. Nonetheless, these preliminary, random-assignment, double-blind clinical data suggest that bedtime administration of quetiapine among patients stabilized at their therapeutic dosage is clinically feasible. A switch to once-daily quetiapine administration can be considered both for the convenience of the subject and to improve adherence to long-term treatment. However, it must be emphasized that these data do not suggest “drug holidays” are good clinical practice but really that administration frequency based on plasma half-lives may not necessarily be valid for all antipsychotic agents. AcknowledgementsWe thank Ms R Atzert and Ms T Anderson for recruitment and study coordination and data entry. We also thank Dr A Gopalani, Dr R Davis, Dr S Karp, and Mr R Kuppelweiser for facilitating this study. References1. Arvanitis LA, Miller BG. Multiple fixed doses of “Seroquel” (quetiapine) in patients with acute exacerbation of schizophrenia: a comparison with haloperidol and placebo. The Seroquel Trial 13 Study Group. Biol Psychiatry 1997;42:233–46. 2. Small JG, Hirsch SR, Arvanitis LA, Miller BG, Link CG. Quetiapine in patients with schizophrenia. A high- and low-dose double-blind comparison with placebo. Seroquel Study Group. Arch Gen Psychiatry 1997;54:549–57. 3. DeVane CL, Nemeroff CB. Clinical pharmacokinetics of quetiapine: an atypical antipsychotic. Clin Pharmacokinet 2001;40:509–22. 4. King DJ, Link CGG, Kowalcyk B. A comparison of bd and tid dose regimens of quetiapine (Seroquel) in the treatment of schizophrenia. Psychopharmacology 1997;137:139–46. 5. Kapur S, Seeman P. Does fast association from the dopamine D2 receptor explain the action of atypical antipsychotics? A new hypothesis. Am J Psychiatry 2001;158:360–9. 6. American Psychiatric Association. Diagnostic and statistical manual of mental disorders: DSM-IV, 4th ed. Washington (DC): American Psychiatric Association, 1994. 7. Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 1987;13:261–76. 8. Guy W. Clinical global impressions. ECDEU assessment manual for psychopharmacology. Rockville (MD): US Department of Health, Education and Welfare; 1976; p 217–22. 9. Hamilton M. Development of a rating scale for primary depressive illness. Br J Soc Clin Psychol 1967;6:278–96. 10. Simpson GM, Angus JWS. A rating scale for extrapyramidal side effects. Acta Psychiatr Scand 1970;212(Suppl):11–9. 11. Barnes TRE. A rating scale for drug induced akathisia. Br J Psychiatry 1989;154:672–6. 12. Guy W. Abnormal involuntary movement scale (AIMS). ECDEU assessment manual for psychopharmacology. Rockville (MD): US Department of Health, Education, and Welfare; 1976; p 534–7. 13. Schooler NR, Kane JM. Research diagnoses for tardive dyskinesia. Arch Gen Psychiatry 1982;39:486–7. 14. Chouinard G, Sultan S. Treatment of supersensitivity psychosis with antiepileptic drugs: report of a series of 43 cases. Psychopharmacol Bull 1990;26:337–41. 15. Chouinard G. Severe cases of neuroleptic-induced supersensitivity psychosis. Diagnostic criteria for the disorder and its treatment. Schizophr Res 1991;5:21–33. 16. Chouinard G, Vainer JL, Belanger MC, Turnier L, Beaudry P, Roy JY, and others. Risperidone and clozapine in the treatment of drug-resistant schizophrenia and neuroleptic-induced supersensitivity psychosis. Prog Neuropsychopharmacol Biol Psychiatry 1994;18:1129–41. 17. Ahmed S, Chengappa KNR, Naidu VR, Baker RW, Parepally H, Schooler NR. Clozapine withdrawal emergent dystonias and dyskinesias: a case series. J Clin Psychiatry 1998;59:472–7. 18. Kapur S, Zipursky R, Jones C, Shammi CS, Remington G, Seeman P. A positron emission tomography study of quetiapine in schizophrenia: a preliminary finding of an antipsychotic effect with only transiently high dopamine D2 receptor occupancy. Arch Gen Psychiatry 2000;57:553–9. 19. Farde L, Nordstrom AL, Wiesel FA, Pauli S, Halldin C, Sedvall G. Positron emission tomographic analysis of central D1 and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine. Relation to extrapyramidal side effects. Arch Gen Psychiatry 1992;49:538–44. 20. Tauscher-Wisniewski S, Kapur S, Papatheodorou G, Jones C, Daskalakis ZJ, Zipursky RB. Quetiapine in first episode schizophrenia: treatment effects and PET evaluation. Schizophr Res 2001;49(Suppl 1–2):247. Author(s)Manuscript received November 2001, revised, and accepted September 2002. Previously presented as a poster at the 40th Annual Meeting of the American College of Neuropsychopharmacology; December 13–19, 2001; Waikoloa (HI). 1. Staff Psychiatrist, Mayview State Hospital, Bridgeville, Pennsylvania. 2. Consulting Statistician, Pittsburgh, Pennsylvania. 3. Director, Clinical Research, AstraZeneca LP, Wilmington, Delaware. 4. Clinical Research Manager, AstraZeneca LP, Wilmington, Delaware. 5. Director, Clinical Science - CNS, AstraZeneca LP, Wilmington, Delaware. Address for correspondence: Dr KN Roy Chengappa, MD, Mayview State Hospital, 1601 Mayview Road, Bridgeville, PA 15017-1599
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