International Consensus Study of Antipsychotic Dosing psychotic drugs are required to guide clin- ical dosing as well as design and interpret reference, estimated clinical equivalency research studies. Available dosing guide- lines are limited by the methods and data for sulpiride to 10.0 for trifluperidol. Sev- istics, including age, hepatic and renal Method: With a two-step Delphi method, the authors surveyed a diverse group function, stage and illness severity, sex, mined median clinical dosing equivalents ed for selected clinical circumstances.
cally employed antipsychotic drugs. They can support clinical practice, trial design, disorders for 37 oral agents and 14 short- (Am J Psychiatry Gardner et al.; AiA:1–8) Clinical management of antipsychotic drug treat- based survey of research and clinical experts. We aimed to ment is increasingly complex, with growing numbers and develop an internationally representative set of clinically applications of clinically employed agents, inconclusive equivalent dosing estimates and dosing recommenda- findings among treatment efficacy and effectiveness trials tions for most clinically employed first- and second-gen- involving first- or second-generation antipsychotic drugs, and polytherapy with complex drug combinations (1–12). Despite growing clinical and research requirements for reliable dosing estimates, available dosing guidelines rest on a severely limited research base (2, 13–18). Proposed schemes usually are based on averages of doses recom- We identified colleagues with experience in clinical research mended by manufacturers and approved by regulatory and in the clinical use of antipsychotic drugs, based on prelimi- bodies or on expert-estimates of approximate clinically nary literature searches, reputation among peers, and by investi- equivalent potency (2, 13, 19). It would be desirable to gator consensus. We sought geographically and demographically base such potency comparisons on randomized, especial- diverse participation. Research experts were considered eligible only if they had at least five peer-reviewed publications related ly head-to-head, comparisons of a range of antipsychot- specifically to clinical trials of antipsychotic drugs. Clinical ex- ics at several fixed doses, and across various diagnostic, perts were referred by participating research experts as particu- illness severity, comorbidity, and demographic variables. larly knowledgeable in the use of antipsychotic medicines, with However, currently available information arising from extensive clinical practice experience.
research of this kind is severely limited, and such stud- ies remain rare (17, 20, 21). Uncertainties about clinically The survey instrument included three sections: [A] clini- equivalent doses of antipsychotics probably contribute to cally equivalent doses; [B] dosing recommendations; and [C] apparent variance in efficacy and tolerability in clinical dosing adjustments for specific, defined, circumstances. In practice and to inconsistent findings among experimental section A, participants were to estimate the clinically equiva- lent dose of 59 antipsychotic preparations, including 36 orally administered agents and 13 short-acting and 10 long-acting Given the unsatisfactory evidence base to define clini- injected agents. Clinical scenarios used olanzapine, 20 mg/ cally equivalent doses and dosing range recommenda- day, as the reference treatment for the equivalency estimates tions of available antipsychotics for both clinical and re- of the oral and long-acting injectable agents. We calculated the search applications, we used a Delphi method (26, 27) of dosing ratios to this dose of olanzapine and to the equivalent consensus building in a broad, two-stage, questionnaire- dose for chlorpromazine as a historical reference. Injectable TABLE 1. Clinical Dosing Equivalencies and Dosing Recommendations of Oral Antipsychotics a Respondents were asked what dose they consider to be clinically equivalent to 20 mg/day of olanzapine in treatment of the reference case, a moderately symptomatic man with DSM-IV schizophrenia with ≥2 years of antipsychotic treatment and not considered treatment refractory. Median confidence levels for the clinically equivalent doses are reported as low (L), moderate (M), or high (H). b Respondents were asked to indicate their usual starting dose, target dosing range, and maximum daily dose for the reference case after being untreated for over 1 month. The target dose range reflects the median lower and upper doses of ranges recommended. haloperidol, 5 mg, was the reference for short-acting inject- ing recommendations based on variance in demographic and able agents. Study participants also rated their confidence in each estimate provided, as high (based on extensive experi- ence; applies to most patients), moderate (some experience; probably applies to most patients), or low (limited experience Following review and approval of the study protocol by the or frequent exceptions based on clinical circumstances). Par- Dalhousie University Health Sciences Research Ethics Board, ticipants were instructed to give priority to efficacy over toler- each study participant provided written, informed consent for participation and public acknowledgment. In 2007–2008, partici- Section B requested usual starting doses, typical target ranges, pants were sent the same study survey instrument electronically and usual maximum doses for the each oral or injectable agent in two stages, based on the iterative Delphi method of consensus- (N=61). Brief, standardized clinical vignettes provided a consis- building, used extensively in social sciences and health research tent context for responses. Typically, vignettes were based on including mental health (26–28). This method provides for in- treatment of adult males with DSM-IV or ICD-10 schizophrenia, dependent input by each participant at both stages, with sum- with ≥2 years of lifetime exposure to antipsychotics and not con- mary information included at stage II based on the averaged, sidered treatment refractory or intolerant. Section C sought dos- collective, and anonymous contributions from stage I. Summary GARDNER, MURPHY, O’DONNELL, ET AL.
TABLE 2. Estimated Dosing Recommendations for Short-Acting Injectable Antipsychotics Dose per Injection Maximum Dose per 24 Hours a Respondents were asked what dose they consider to be clinically equivalent to a single, 5-mg intramuscular dose of haloperidol in treatment of the reference case, an adult man with DSM-IV schizophrenia not treated for 2 weeks, presenting with delusions, auditory hallucinations, agitation, poor cooperation, threatening behavior, and who is refusing oral medications. Median confidence regarding clinically equivalent dosing was reported as moderate for all agents except mesoridazine, prochlorperazine, and trifluopromazine, for which confidence was b Respondents were asked to indicate their usual initial intramuscular dose, the dose range per injection, and the maximum intramuscular dose per 24 hours for the reference case. Range of doses/injection reflects the median lower and upper doses of ranges recommended. information included the means (with standard deviations and and mean oral dosage equivalency estimates were very similar in coefficients of variation), medians (with ranges and interquartile our preliminary assessment (r=0.997, p<0.0001; slope=1.01 [95% ranges), and the median confidence levels of stage I responses CI= 0.985–1.04]), only medians with interquartile range (IQR) are regarding each drug, as well as the number of respondents per reported for simplicity and to limit the impact of potential ex- estimate. Minor adjustments for stage II included addition of treme or outlier values. Coefficient of variation (SD/mean×100) clotiapine, as suggested by several participants, and removal of was used to indicate consensus in final recommendations and spiroperidol and pipothiazine undecylenate for lack of responses was defined empirically as high (≤25%), moderate (26%–33%), in stage I. We also modified section C to request dosing recom- or relatively low (>33%). For oral agents, equivalency ratios were mendations in the presence of common comorbid medical dis- calculated for olanzapine, the reference treatment, and for chlor- orders (diabetes mellitus, ischemic heart disease, organic brain promazine. Statistical analyses employed commercial software syndrome, substantial hepatic or renal impairment) identified by (Stata.8®, Stata Corp, College Station, Tex.; Statview.V®, SAS Corp, Cary, N.C.; and SPSS 15.0 for Windows, Chicago).
First, we evaluated associations of recommended oral doses averaged across all drugs as a continuous variable for each study participant versus a total of nine participant characteristics, in- cluding four continuous variables tested with linear regression (age, years of experience, antipsychotic research studies per par- We obtained agreement to participate from 46 of 111 ticipant, and peer-reviewed publications per participant), with candidates (41.4%); 43 of these participants (93.5%; 32 re- contingency tables to evaluate four categorical variables (sex, searchers, 11 clinicians), representing a wide geographic country, majority of patients treated [in terms of diagnosis and distribution and 18 countries, completed both stages of race/ethnicity], and main career interest [research/clinical] of the Delphi process. The participant group was mostly In addition, we sought recommendations for adjusting oral male (91%). The mean age of the group was 49 years doses of antipsychotics based on the following patient demo- (SD=10). Participants had a mean of 23 years (SD=10) of graphic and clinical characteristics: sex, age, race or ethnicity, experience with antipsychotics and had been involved in a diagnosis, current clinical state, illness severity, illness duration, median of 15 studies with 30 antipsychotic peer-reviewed specific psychiatric comorbidity (substance use or anxiety disor- publications. For their primary interest, 58% specifically ders), medical comorbidity (ischemic cardiac disease, clinically hepatic or renal impairment, diabetes mellitus, delirium, or de- indicated schizophrenia, with 35% more broadly indicat- mentia), abnormally high or low body weight (based on standard ing psychotic or major mood disorders. Their experience BMI criteria provided), and type of oral formulation. For each fac- was primarily with Caucasian patients (72%), East-Asian tor, we evaluated the proportion of participants recommending a (14%), or patients of various races (Asian, black, Cauca- dose change and calculated median percentage changes in dose.
We summarized reported estimates of clinical dosing equiva- lents among agents and clinical circumstances, based on com- Geographically, most respondents were from North parison to standard treatments, as reported in stage II. As median America (U.S. [N=10] or Canada [N=4]) or Western Europe TABLE 3. Clinical Dosing Equivalencies and Dosing Recommendations for Long-Acting Injectable Antipsychotics a Respondents were asked what dose and interval they considered clinically equivalent to oral olanzapine, 20 mg/day, in the treatment of the reference case, a moderately symptomatic man with DSM-IV schizophrenia, not considered treatment-refractory with ³2 years of anti- psychotic treatment. The reported clinically equivalent doses are adjusted to correspond to the median dosing interval. Confidence in the clinically equivalent dose was moderate for all agents. b Initial and maximum doses are adjusted to match the median dosing intervals. Target dose range reflects the median lower and upper doses (Italy [N=4], Spain [N=4], Austria [N=2], Denmark [N=2], equivalents was 4.8 mg/day (IQR=1.4); the overall target Germany [N=2], Portugal [N=2], Belgium [N=1], Finland dose range (mean median of lower and upper bounds of [N=1], or United Kingdom [N=1]). Other regions included ranges) was 10.2 to 25.5 mg/day; and the overall mean me- Japan (N=3), Turkey (N=2), and India, Israel, People’s Re- dian maximum dose for oral antipsychotics in olanzapine public of China, Republic of Korea, and Taiwan (N=1 each).
equivalents was 30.9 mg/day (IQR=7.5).
There were no significant differences in estimates of mean or median clinical dosing equivalences among all Each stage of the Delphi process required participants to oral or parenteral antipsychotics between research (N=32) complete up to 59 clinical equivalency estimates and 191 and clinical (N=11) experts. Overall, there was strong dosing recommendations. The consistency of equivalency agreement between participant types regarding clinically estimates improved as the average coefficient of variation equivalent dosing estimates for all agents and formula- decreased from 57% in stage I to 33% in stage II (paired t tions (Pearson r=0.979). Findings were similar for dosing test between study stages: t=7.20, df=58, p<0.0001). Con- recommendations of oral agents (r=0.991) and for paren- sensus also improved among dosing recommendations teral administration (r=0.959; all p<0.0001).
(starting, target, and maximum), with moderate or high Factors Associated With Dosing Recommendations consensus (coefficient of variation<33%) rising from 29% Preliminary bivariate analyses for effects on starting and to 47% between stages I and II. Final consensus, based on maximum recommended daily oral doses related to eight moderate or high median levels of agreement (coefficient participant characteristics (sex, age, years of experience, of variation<33%), was 76.3% overall for equivalency esti- antipsychotic studies and publications/person, country, mates (long-acting injected agents: 90%; oral agents: 83%; major diagnostic type of patients treated, and main career short-acting injected agents: 46%) and 67% for all dosing interest [research/clinical]) revealed no significant associ- recommendations (oral agents: 69%; short-acting injected ations. Since no factor was sustained as important in these agents: 67%; long-acting injected agents: 60%). Median initial analyses (not shown) we did not pursue multivari- dosing recommendations (mg/day) were 5.8% lower in stage II, reflecting changes in 28.7% (N=74 of 258) of initial Several patient factors did affect dosing recommenda- tion (Table 4). As expected, age had a major effect in that Clinically Equivalent Dose Estimates and recommended median daily oral antipsychotic doses were 60%, 30%, and 50% lower in children, adolescents, and the Clinically equivalent antipsychotic dosing recommen- elderly, respectively, than in young adults. Selected medi- dations were obtained for oral agents (N=36 [Table 1]), cal comorbidities (e.g., diabetes, heart disease, hepatic or short-acting injectable agents (N=13 [Table 2]), and long- renal impairment, organic brain syndrome) also led to acting injectable agents (N=10 [Table 3]) formulations. 10%–45% lower recommended median daily oral doses Based on data reported (Table 1), the overall mean me- relative to adult patients without such illnesses. Respon- dian starting dose for oral antipsychotics in olanzapine dents recommended an average of 20% lower daily anti- GARDNER, MURPHY, O’DONNELL, ET AL.
TABLE 4. Factors for Which Antipsychotic Dosing Changes Are Recommendeda a Reported are numbers of responses and percentage of respondents recommending dosing changes, ranked by median magnitude and direction (decrease or increase) of recommended daily oral dose adjustments, for factors deviating from the reference case, a moderately symptomatic Caucasian man (age 35 years) of normal weight with DSM-IV schizophrenia, not considered refractory, with >2 years of an- tipsychotic treatment but untreated for 1–3 months. Other patient characteristics not considered to require dosing adjustment included being overweight (BMI 25–30 kg/m2) or obese (BMI >30.0); being black or Hispanic; ≥15 years of illness and antipsychotic drug use; being hospitalized versus ambulatory; disorders other than schizophrenia (schizoaffective, delusional, manic or mixed states of bipolar disorder, or unspecified psychosis); comorbid substance use or anxiety disorders; average clinical quality of prior antipsychotic treatment responses; rapid-dissolving tablet, oral liquid, or long-acting (depot) injected formulations.
psychotic doses for East-Asian versus Caucasian patients, reduction by 20% was recommended for short-acting in- even though dosing recommendations for the partici- jected preparations relative to oral preparations (Table 4).
pant’s predominant race/ethnicity of patients treated was not significantly associated with dosing recommenda- tions (data not shown). Recommended daily doses aver-aged 10% lower for adult women than for men. For under- Broadly representative and plausible recommendations weight patients, based on standard BMI criteria (<18.5 kg/ of clinically equivalent doses for antipsychotic drugs are m2), recommended doses were 20% lower than for normal needed to guide clinical dosing decisions, design of re- weight patients (BMI=18.5–20.0 kg/m2) but were not af- search studies, and interpretation of research findings (2, fected significantly for overweight patients (BMI>20 kg/ 4, 5, 22–25). Accordingly, this study employed a Delphi, m2). Dosing recommendations were not affected by co- two-stage, international survey of experienced and ex- morbid anxiety or substance use disorders.
pert clinical and research colleagues to gain consensus Several factors related to psychiatric illness were associ- estimates of clinically equivalent doses (compared to oral ated with dosage modifications, although dosing was sim- olanzapine or short-acting injectable haloperidol as stan- ilar for most forms of psychotic or manic illness. However, dards). Dosing recommendations (starting dose, typical bipolar depression or long-term prophylactic treatment target range, and maximum daily doses) of currently clini- of currently euthymic bipolar disorder patients called for cally employed oral and parenteral antipsychotics were dose reductions averaging 25% below the similar recom- also sought using the same method along with consensus mendations for acute mania or exacerbated schizophre- recommendations for their modification under specific nia. Severe, acute psychotic illness or a history of unsatis- factory treatment response led to recommended increases This is a first application of the otherwise widely em- of daily antipsychotic dose by an average of 25%, whereas ployed Delphi method for seeking consensus to estimate mild symptoms and first-episode of psychotic illness led equivalent doses of antipsychotics. Effectiveness of the to 25%–30% lower recommended doses than for repeated- two-stage Delphi method used is indicated by decreases ly acutely psychotic patients, with no distinction between in the variance of dose estimates between survey stages, acute and chronic illnesses. There were no appreciable dif- and by achieving an average rate of 76% consensus in final ferences in recommended dosing for hospitalized versus (stage II) clinical equivalency estimates and 67% for all dos- ambulatory patients diagnosed with reasonably clinically ing recommendations. Over several decades, there have stable, chronic schizophrenia. Drug formulations also been efforts to estimate equivalent doses of antipsychotic had no effect on recommended doses, except that dosage and other psychotropic drugs. Typically, these recom- mendations have considered limited ranges of agents and reported by Davis and Chen (17), we found a strong cor- made use of findings from flexible-dose trials with varying relation between their near-maximally effective doses and ranges of permitted doses and clinically determined doses the equivalent doses in our survey among 10 oral antipsy- (13–18). Such recommendations risk confounding-by-in- chotics common to both investigations (Pearson’s r=0.890, dication and regression-to-mean artifacts and have led to sometimes strikingly inconsistent recommendations. No- Other proposals to establish drug potency equivalents tably, the World Health Organization (WHO) system of ex- include use of plasma or serum concentrations of antipsy- pert consensus-based recommendations of defined daily chotic drugs and their major active metabolites, or mod- doses for antipsychotics identified 10 mg/day of olanzap- ern brain imaging methods to estimate levels of receptor ine as the average maintenance dose for adult patients occupancy, usually involving competition for dopamine diagnosed with schizophrenia (18, 29); this is a conserva- D receptors labeled with positron-emitting, selective ra- tive dose for many psychotic patients (2, 3, 7). We used 20 dioligands (30–32). Although theoretically attractive, such mg/day of olanzapine as a standard reference treatment methods are costly and technically challenging, and at on which to base the reported clinically equivalent dos- best indirect correlates of clinical response that may be ing estimates. Based on this difference in recommended especially questionable with respect to the limited D - doses of olanzapine, it is not surprising that the average antagonistic actions of some commonly used, second- equivalent dose among oral agents was 50% higher (1.5 ± generation antipsychotic agents (2, 30–34).
1.6 times greater) in this study than in WHO-defined daily The present study identified several patient characteris- dose recommendations, although these sets of equivalent tics leading to recommended dosage adjustments (Table doses are strongly correlated (r=0.920).
4), notably including substantial lowering of doses for Fixed-dose, randomized trials involving multiple active geriatric and pediatric patients, and increases for cases comparators at a wide range of doses are required to es- involving severe psychotic symptoms and dysfunction. timate dosing equivalencies objectively and provide sci- These dosing recommendations appear to have face va- entifically secure dosing recommendations. Considering lidity in that they are consistent with currently standard the highly varied indications for antipsychotics and great clinical practices. The specific consensus recommenda- heterogeneity of patients and their treatment responses, tion to reduce doses of antipsychotic drugs for East Asian required studies would need to be either very large or re- patients by approximately 20% relative to Caucasians (Ta- peated several times in dissimilar patient populations. ble 4) is consistent with some but not other reports con- Based on the limited available fixed-dose data, Davis and cerning comparative dosing across races, and was not as- Chen (17) attempted in 2004 to estimate the near maxi- sociated with the predominant race/ethnicity of patients mal effective dose of antipsychotics by generating dose- usually treated by study participants, leaving the question response curves. Their findings demonstrate the limita- tions associated with this method. For oral antipsychotics, This study has several limitations. Although the range of the computed near-maximally effective dose varied by geographic sites and professional experiences represent- 50% to 300% for only seven antipsychotics, with striking ed is quite broad, several regions of the world, especially variance among individual dose responses for most drugs. Central and South America, much of Eastern Europe, and For four agents they could only provide a threshold dose parts of the Middle East, Africa, and south-central Asia are in which the near maximal effective dose was estimated notably unrepresented, and the sample comprised mostly to be above or below. For these drugs, limitations in the male physicians despite efforts to recruit more women. A data failed to indicate at which dose the response curve more substantive limitation is the lack of objective stan- plateaus. In only three cases were they able to report a dards by which to select standard comparator doses, and single oral dose as the “near maximal effective dose” (ami- to verify what are essentially clinical impressions, even sulpride, 200 mg; aripiprazole, 10 mg; and risperidone, though provided collectively and systematically by ex- 4 mg). These estimates were based on findings with sig- perts. Experience-based dosing opinions are susceptible nificant heterogeneity or minimal datapoints. With these to many influences, including uncritically accepted lo- limitations, it is not impossible currently to firmly deter- cal dosing practices, inaccurate representations of per- mine clinically equivalent doses of antipsychotics based sonal practices, or inaccurate dosing recommendations on randomized, controlled, and blinded fixed-dose trials by manufacturers in the regulatory approval process. In involving more than one drug, a placebo, and patients of addition, the results assume, unrealistically, that clinical specific types. This state of current knowledge is not sur- antipsychotic dosing is constant and uniform among di- prising considering the heterogeneity of clinical presen- agnoses, under changing and typically unstable clinical tations and of treatment responses, even among patients conditions, and in often subtly differing forms or levels of with nominally identical DSM or ICD diagnoses, long rec- symptomatic severity. In addition, several uncommonly ognized by clinicians and researchers, and elegantly noted clinically used agents received relatively few responses by Davis and Chen (17). Despite these limitations and us- from study participants (Table 1). Median doses and their ing the midpoint dose (estimated median) of the ranges variance are reported so as to minimize effects of outlier GARDNER, MURPHY, O’DONNELL, ET AL.
er (U.S.), Massimo Mauri (Italy), Vicente Molina (Spain), Dieter Naber values, and they were remarkably similar to mean doses. (Germany), Evaristo Nieto (Spain), Kensuke Nomura (Japan), Dost Moreover, there is a tacit, but unrealistic, pharmacologi- Öngür (U.S.), Linda Peacock (Denmark), Gary Remington (Canada), cal assumption of linearity of dosing across a broad range Christian Simhandl (Austria), Rael Strous (Israel), Takefumi Suzuki (Ja-pan), Jari Tiihonen (Finland), JK Trivedi (India), Eduard Vieta (Spain), of doses and across many dissimilar drugs that can be Miguel Xavier (Portugal), A. Elif Anil Yagcioglu (Turkey), and Nevzat captured adequately with an estimated, consensus ratio of potency to a single, selected dose of a standard agent such as olanzapine or chlorpromazine (2, 14, 17; Tables 1–3). Despite these and other limitations, we present the findings of this international survey as a representation of 1. Leslie DL, Rosenheck RA: From conventional to atypical an- substantial and systematically acquired expert consensus. tipsychotics and back: dynamic processes in the diffusion of The findings should provide at least approximate and gen- new medications. Am J Psychiatry 2002; 159:1534–1540 eral guidelines to support clinical dosing as well as plan- 2. Baldessarini RJ, Tarazi FI: Pharmacotherapy of psychosis and ning and interpretations of experimental therapeutics tri- mania, in Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 11th ed. Edited by Brunton LL, Lazo JS, Parker KL. New York, M cGraw-Hill, 2005, pp 461–500 In conclusion, the reported findings arise from a large, 3. Lieberman JA, Stroup TS, M cEvoy JP, Swartz M S, Rosenheck RA, systematic, international survey using Delphi methods to Perkins DO, Keefe RS, Davis SM , Davis CE, Lebowitz BD, Severe J, develop consensus. It provides general guidelines for ap- Hsiao JK (Clinical Antipsychotic Trials of Intervention Effective- proximately clinically equivalent recommended doses of a ness (CATIE) Investigators): Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J M ed 2005; broad range of clinically employed, modern and older an- tipsychotics, including both oral and parenteral formula- 4. Gardner DM , Baldessarini RJ, Waraich P: M odern antipsychotic tions. The study also provides recommendations from clin- drugs: a critical overview. CM AJ 2005; 172:1703–1711 ical and research experts on modification of dosing based 5. Heres S, Davis J, M aino K, Jetzinger E, Kissling W, Leucht S: Why on specific demographic or clinical characteristics of pa- olanzapine beats risperidone, risperidone beats quetiapine, and quetiapine beats olanzapine: an exploratory analysis of tients for whom antipsychotics are commonly employed.
head-to-head comparison studies of second-generation anti-psychotics. Am J Psychiatry 2006; 163:185–194 6. Jones PB, Davies L, Barnes TR, Dunn G, Lloyd H, Hayhurst KP, Received June 8, 2009, revision received Oct. 5, 2009; accepted M urray RM , M arkwick A, Lewis SW: Randomized controlled Nov. 30, 2009 (doi: 10.1176/appi.ajp.2009.09060802). From the De- trial of effect on quality of life of second-generation versus first partment of Psychiatry, College of Pharmacy, and School of Nurs- generation antipsychotic drugs in schizophrenia. Arch Gen Psy- ing, Dalhousie University; Department of Psychiatry, Harvard Medi- cal School and International Bipolar & Psychotic Disorders Research 7. Centorrino F, Cincotta SL, Talamo A, Fogarty KV, Guzzetta F, Consortium, McLean Division of Massachusetts General Hospital, Saadeh M G, Salvatore P, Baldessarini RJ: Hospital use of anti- Boston. Address correspondence and reprint requests to Dr. Gardner, psychotic drugs: polytherapy. Compr Psychiatry 2008; 49:65–69 Department of Psychiatry & College of Pharmacy, Dalhousie Univer-sity, QEII HSC, Abbie Lane Bldg. 7517, 5909 Veterans’ Memorial Lane, 8. Domino M E, Swartz M S: Who are the new users of antipsychot- Halifax, N.S., Canada, B3H 2E2; (e-mail).
ic medications? Psychiatr Serv 2008; 59:507–514 Dr. Gardner has provided training to employees of AstraZeneca; 9. Goudie AJ, Cole JC: Switching antipsychotics; antipsychotic has participated in advisory boards with Eli Lilly, Janssen-Ortho, and tolerance, withdrawal and relapse: unresolved issues and re- Pfizer Corporations; and leads a project funded by Pfizer. He is not a search implications. J Psychopharmacol 2008; 22:815–817 member of any speakers bureaus. Dr. Centorrino receives research 10. Lewis S, Lieberman J: CATIE and CUtLASS: can we handle the support from Teva Pharmaceuticals, is an advisor to Janssen, and is a truth? Br J Psychiatry 2008; 192:161–163 member of speakers bureaus for AstraZeneca, Bristol-Myers Squibb, 11. Leucht S, Corves C , Arbter D, Engel RR, Li C , Davis JM : Second- Eli Lilly, Janssen, Johnson & Johnson, and Pfizer Corporations. Dr. generation versus first-generation antipsychotic drugs for Baldessarini has recently been a consultant or investigator-initiated research collaborator with AstraZeneca, Auritec, Biotrofix, Janssen, schizophrenia: meta-analysis. Lancet 2009; 373:31–41 JDS-Noven, Lilly, Luitpold, NeuroHealing, Novartis, Pfizer, and SK-Bio- 12. Parks J, Radke A, Parker G, Foti M E, Eilers R, Diamond M , Svend- Pharmaceutical Corporations; he is not a member of pharmaceutical sen D, Tandon R: Principles of antipsychotic prescribing for speakers bureaus. Dr. Murphy and Ms. O’Donnell report no financial policy makers, circa 2008. translating knowledge to promote relationships with commercial interests. None of the authors or their individualized treatment. Schizophr Bull 2009; 35:931–936 immediate family members holds equity positions in biomedical or 13. Davis JM : Comparative doses and costs of antipsychotic medi- cation. Arch Gen Psychiatry 1976; 33:858–861 Supported by the Department of Psychiatry Research Fund, Dal- 14. Baldessarini RJ, Cohen BM , Teicher M H: Significance of neuro- housie University (to Dr. Gardner), a grant from the Bruce J. Anderson leptic dose and plasma level in the pharmacological treatment Foundation, and by the McLean Private Donors Psychopharmacol-ogy Research Fund (to Dr. Baldessarini). of psychoses. Arch Gen Psychiatry 1988; 45:79–91 The authors thank study participants (all of whom consented to be 15. Rijcken C , M onster T, Brouwers J, de Jong-van den Berg LT: named): Drs. A. Carlo Altamura (Italy), Jose A. Apud (U.S.), A. George Chlorpromazine equivalents versus defined daily doses: how Awad (Canada), Ross J. Baldessarini (U.S.), Corrado Barbui (Italy), Dan- to compare antipsychotic drug doses? J Clin Psychopharmacol iel Casey (U.S.), Franca Centorrino (U.S.), Siow-Ann Chong (Singapore), Young-Chul Chung (Republic of Korea), Benedicto Crespo-Facorro 16. Woods SW: Chlorpromazine equivalent doses for the newer (Spain), John M. Davis (U.S.), Marc De Hert (Belgium), W. W olfgang atypical antipsychotics. J Clin Psychiatry 2003; 64:663–667 Fleischhacker (Austria), David Gardner (Canada), John Geddes (United 17. Davis JM , Chen N: Dose response and dose equivalence of anti- Kingdom), Birte Glenthoj (Denmark), Donald Goff (U.S.), Ricardo Gus- psychotics. J Clin Psychopharmacol 2004; 24:192–208 mao (Portugal), Giuseppe Imperadore (Italy), Philip G. Janicak (U.S.), Yasuhiro Kaneda (Japan), Alain Labelle (Canada), Hsien-Yuan Lane 18. Nosè M , Tansella M , Thornicroft G, Schene A, Becker T, Veronese (Taiwan), Stefan Leucht (Germany), John Luo (U.S.), Stephen R. Mard- A, Leese M , Koeter M , Angermeyer M , Barbui C: Is the defined daily dose system a reliable tool for standardizing antipsychotic 28. Langlands RL, Jorm AF, Kelly CM , Kitchener BA: First aid recom- dosages? Int Clin Psychopharmacol 2008; 23:287–290 mendations for psychosis: using the Delphi method to gain 19. Bezchlibnyk-Butler KZ, Jeffries JJ: Clinical Handbook of Psycho- consensus between mental health consumers, carers, and cli- tropic Drugs, 17th rev ed. Seattle, Hogrefe & Huber, 2007 nicians. Schizophr Bull 2008; 34:435–443 20. Leucht S, Arbter D, Engel RR, Kissling W, Davis JM : How effec- 29. World Health Organization Collaborating Centre for Drug Sta- tive are second-generation antipsychotic drugs? meta-analysis tistics M ethodology: ATC/DDD Index 2009. http://www.whocc.
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When Is the Statute of Limitations a Defense? I) Definition of “statute of limitations.” A statute of limitations sets forth the time within which an accrued cause of action must be asserted in court. If the plaintiff brings a cause of action after the statute of limitations has run,he/she has no legal remedy. The statute of limitations is an affirmative defense that must be pled byt

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