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Presented by Dr Pavan kumar Chair Person: Dr Denzil Pinto

Stanley N. Caroff, MD; Vicki G. Davis, DrPH; Del D. Miller, PharmD, MD; Sonia M. Davis, DrPH; Robert A. Rosenheck, MD; Joseph P. McEvoy, MD; E. Cabrina Campbell, MD; Bruce L. Saltz, MD; Silvana Riggio, MD; Miranda H. Chakos, MD; Marvin S. Swartz, MD; Richard S. E. Keefe, PhD; T. Scott Stroup, MD, MPH; and Jeffrey A. Lieberman, MD, for the CATIE Investigators

Stanley N. Caroff, MD,

Veterans Affairs Medical Center-116A, University & Woodland Avenues, Philadelphia, PA 19104 email: stanley.caroff@va.gov
Journal of Clinical Psychiatry 2011;72(3):295303

Supported by Clinical Antipsychotics Trials of

Intervention Effectiveness project(CATIE), National Institute of Mental Health. Study based on results from CATIE.

The Clinical Antipsychotic Trials of Intervention

Effectiveness project (CATIE) is a research project to evaluate the clinical effectiveness of atypical antipsychotics in the treatment of schizophrenia and Alzheimer's disease.

Previous published studies are Predominantly short-term studies designed for regulatory approval and labeling language. Comparators are either placebo or a single active agent (usually haloperidol) Results have limited generalizability because they lack representative patient samples, clinical settings and treatment conditions Existing studies do not address critical clinical and policy questions Sponsored by pharmaceutical companies

DSM-IV schizophrenia,

18-65 years old


Not first-episode or treatment resistant Concomitant medications, medical illnesses,

substance use disorders allowed Conducted at 57 geographically, demographically and organizationally diverse sites

How do the second generation antipsychotics

compare with a representative first generation antipsychotic? What is the comparative effectiveness of the second generation antipsychotic drugs? Are the second generation antipsychotics cost-effective?

Participants 1600 people with schizophrenia Trial duration Subjects participate for 18 months Design Practical trial that is a hybrid of efficacy and effectiveness trial designs

Overall, the medications were comparably effective but

were associated with high rates of discontinuation due to intolerable side effects or failure to adequately control symptoms. Olanzapine, was slightly better than the other drugs but also was associated with significant weight-gain as a side-effect The older, less expensive medication (perphenazine) used in the study generally performed as well as the four newer medications

The newer medications have no substantial advantage

over the older medication used in this study. An important issue still to be considered is individual differences in patient response to these drugs

NIMH Clinical Antipsychotic Trials of Intervention Effectiveness Study (CATIE) Phase 1 Results

Abnormal, involuntary movements of the tongue,

jaw, trunk, or extremities that develop in association with the use of neuroleptic medication. The movements are present over a period of at least 4 weeks and may be choreiform (rapid, jerky, nonrepetitive), athetoid (slow, sinuous, continual), or rhythmic (e.g., stereotypies) in nature.

The signs or symptoms develop during exposure to

a neuroleptic medication or within 4 weeks of withdrawal from an oral (or within 8 weeks of withdrawal from a depot) neuroleptic medication.
There must be a history of the use of neuroleptic

medication for at least 3 months (or 1 month if age 60 years or older).

The movements must not be due to a neurological

or other general medical condition


(e.g., Huntington's disease, Sydenham's chorea, spontaneous dyskinesia, hyperthyroidism, Wilson's disease), to ill-fitting dentures, or to exposure to other medications that can cause acute reversible dyskinesia (e.g., L-dopa, bromocriptine).

The movements should also not be better

accounted for by a neuroleptic-induced acute movement disorder


(e.g., Neuroleptic-Induced Acute Dystonia, Neuroleptic-Induced Acute Akathisia).

The likelihood of tardive dyskinesia (TD) being

irreversible served as a major impetus in antipsychotic drug development. Although controversy arose over the severity and reversibility of TD, a consensus emerged that TD followed a persistent or fluctuating course, but gradually stabilized or diminished, with few patients showing progression.

Data on the change in prevalence of TD during

treatment have been inconclusive, with some studies showing an increase and others, a decrease or no change at all.
Although estimates have varied, roughly 50% of

patients have persistent TD symptoms, 10% to 30% have a reduction in symptoms, and 10% to 30% show increased symptoms during treatment.

Long-term studies estimated that from 2% to 23% of

patients show loss of observable TD symptoms during treatment with first generation drugs(FGAs). Similarly, studies of second-generation agents have shown reduction of TD ratings, with some showing greater reductions, lesser reductions or no difference compared with first-generation agents.

Several cross-sectional studies have found an association

between TD and severity of cognitive deficits , as well as positive and negative symptoms of schizophrenia. Several prospective studies have shown that the presence of TD in schizophrenia correlates with poor response to treatment, lower rates of symptom remission , longer hospital stays , greater risk of relapse ,lower quality of life and functioning, a progressive course, and higher mortality. TD may be a phenotypic manifestation of a more severe, chronic , and refractory subtype of schizophrenia.

Because medication withdrawal risks relapse in

schizophrenia, it became important to examine the course of TD while maintaining antipsychotic treatment. Studying the course of TD in parallel with clinical symptoms is also important because of evidence suggesting an association between TD, symptom severity, treatment response, and prognosis of schizophrenia.

the patients with TD at baseline are more likely to

discontinue treatment for any cause compared with non-TD patients; the course of TD varies among individuals; and there are no differences between second-generation antipsychotics in the outcome of dyskinesias or symptoms of schizophrenia in patients with TD.

STUDY SETTING AND DESIGN Post hoc study analysis based on the CATIE Schizophrenia Trial 57 US sites Between January 2001 and December 2004

The CATIE Schizophrenia Trial offered the

opportunity to examine treatment response in a large sample of schizophrenia patients with TD at baseline randomly assigned to receive second-generation antipsychotics compared to patients without TD in the setting of a controlled trial. In addition, allowed to delineate the course of TD during treatment with second-generation antipsychotics, thereby enabling the development of treatment recommendations for management of symptoms of both schizophrenia and dyskinesias in patients with existing TD.

Treatment phases

Phase 1: patients were randomly assigned to receive

olanzapine, perphenazine, quetiapine, risperidone, or ziprasidone under double-blind conditions and studied for up to 18 months or until treatment was discontinued for any reason. Phase 1a : Patients with TD were excluded from randomisation to perphenazine and were assigned to one of the 4 second-generation antipsychotics.

Ziprasidone was approved for use by US FDA during

the trial and was added after 40 % of the patients had been enrolled. The data presented in the current report deal only with the time from initial randomisation until the first medication was discontinued for patients with TD(phase 1a) or without TD(phase 1).

Approved by an institutional review board at each site,

and written informed consent was obtained from all participants or their legally authorized representatives

Included 18-65 years of age Diagnosis of schizophrenia based on DSM 4th ed using SCID

Excluded if they had a Diagnosis of schizoaffective disorder, MR or Other cognitive disorders An unstable and serious medical condition Past adverse reactions to proposed treatments Treatment resistant schizophrenia First episode of schizophrenia Pregnant or Breast feeding

Total 1493 pts enrolled

33 pts excluded prior to analysis due to concerns about

data integrity 17 patients randomized did not take study medications 212 patients with TD but 12 of these were randomly assigned inadvertently to perphenazine and were excluded from the analysis.

200 patients randomly assigned to receive SGAs ,

who met modified Schooler-Kane criteria for TD at baseline having at least 1 AIMS item with a value of 3, or at least 2 items with a value of 2 at the baseline visit.

A comparison (non-TD) group consisted of 997 pts

assigned to receive SGA who didnt meet modified Schooler-Kane criteria for TD at baseline 67 pts had a h/o TD and 68 pts had 1 AIMS item rated 2 and excluded from secondary supportive analysis, yielding more restricted comparison group (n=862).

Identical-appearing capsules contained olanzapine

(7.5mg),quetiapine(200mg),risperidone(1.5mg),perph enazine(8mg), or ziprasidone (40 mg). Flexibly dosed with 1 to 4 capsules daily. Gradual transition to study medication over first few weeks. Concomitant medications were permitted, except for additional antipsychotics.

Modified Schooler-Kane criteria for TD using

Abnormal Involuntary Movement Scale


Positive and Negative Syndrome Scale (PANSS) Simpson-Angus Abbreviated Scale(SAS)

Barnes Akathisia Scale(BAS)

Basic socio-demographic data were recorded at baseline.

Screened for alcohol and drug abuse treatment with antipsychotics and anti-cholinergics, duration of illness Severity of symptoms measured using tools described
Clinical measures were collected at baseline, month 1,

month 3, and quarterly thereafter 18 months or time of treatment discontinuation.

Cognitive functioning was measured at baseline and

months 2, 6, and 18 by completing 11 neurocognitive tests, 5 neurocognitive domain scores were calculated from 9 neurocognitive test summary scores and standardized to create Z-scores for each domain. A neurocognitive composite score was calculated by creating Z-score of the average of the 5 standardized domain scores.

Primary clinical outcome measure time to all-cause treatment discontinuation, Secondary outcomes discontinuations for intolerability, inefficacy and patient decision; rates of discontinuations; mean modal dose; Change from baseline in the PANSS and neuro-cognitive composite scores. For all clinical measures, supportive analysis were also conducted (in which 135 patients with evidence of TD were excluded from non-TD group).

Kaplan-Meier survival curves

ANCOVA
Bonferroni correction for multiple corrections Chi square tests

nQuery Advisor

Patients Characteristics at Baseline: Compared with non-TD patients at baseline ,patients with TD were significantly older, with longer antipsychotic treatment but fewer recent exacerbations; higher ratings of symptom severity and acute EPS, lower neurocognitive scores; and were more likely have received anticholinergics, antipsychotics in general and first- generation antipsychotics

and DISCUSSION

RESULTS Compared with non-TD patients at baseline ,patients with TD were significantly older and chronically ill, with longer antipsychotic treatment but fewer recent exacerbations; higher ratings of symptom severity and acute EPS, lower neurocognitive scores; and were more likely have received anticholinergics, antipsychotics in general and first- generation antipsychotics

DISCUSSION

Effects of age and duration of illness were adjusted for clinical analysis. Patients with severe symptoms may receive higher drug doses for long periods, with poor adherence, resulting in greater incidence of TD and EPS.

TD patients with higher acute EPS were likely to receive anticholinergics at baseline contributing to impaired cognition.

There was no significant difference between TD and non-TD

groups in time to discontinuation for any cause . No significant differences between groups in time to discontinuation due to efficacy, intolerability or patient decision. The rates of discontinuation were identical between the groups The median time to discontinuation was 4.7 months for the TD group versus 5.4 months for the non-TD group. Discontinuation due to intolerability in the TD group versus the non-TD group was significant only for ziprasidone. Median time to all-cause discontinuation for TD patients receiving SGAs olanzapine>quetiapine>risperidone>ziprasidone

RESULTS No statistical significant TD groupby-treatment interaction for all-cause time to discontinuation . Longer time to discontinuation for any cause on olanzapine compared to other treatments.

DISCUSSION TD by itself is unlikely to affect treatment discontinuation. Previous published study also reports The time to the discontinuation of treatment for any cause was significantly longer in the olanzapine group than in the quetiapine or risperidone group, but not in the perphenazine or ziprasidone group indicating treatment differences were not altered by TD status at baseline.

RESULTS Quitapine was similar to risperidone and ziprasidone in overall effectiveness in both TD and non-TD groups, ie..pts with TD didnt show a more robust response to quetiapine.

DISCUSSION In phase 1b of CATIE, patients with chronic schizophrenia who had just discontinued the older antipsychotic perphenazine for intolerability and acute EPS, quetiapine and olanzapine were more effective than risperidone, as reflected by longer time to discontinuation for any reason suggesting susceptible pts may be less tolerant of drugs likely to acute EPS but not by TD itself.

Discontinuation due to intolerability in the TD group versus the non-TD group was significant only for ziprasidone.

???

No significant change in PANSS score or general

psychopathology between TD and non-TD patient groups. Small but statistically significant difference in neurocognitive composite Z-score at 6 months between TD and non TD patients. Non-TD patients showed significant improvement in verbal memory and processing speed. No significant TD group-by-treatment interactions.

RESULTS

DISCUSSION

No significant change in PANSS score or Greater symptom severity among pts general psychopathology between TD with TD at baseline , similar degree of and non-TD patient groups. improvement in psychopathology compared to non-TD pts, thus proving that the schizophrenia ass with TD has poor response(US-SCAP study) is false when SGAs are used. No significant TD group-by-treatment interactions. Small but statistically significant difference in neurocognitive composite Z-score at 6 months between TD and non TD patients. Treatment with SGAs doesnt differ with TD status. Treatment with SGAs doesnt improve cognition in TD patients.

Mean modal dose

No significant difference between TD groups receiving

different SGAs. Higher mean modal dose of olanzapine for patients with TD(23.65mg) versus those without TD(19.65mg). Overall percentage of patients who received max daily dose of all treatments was nearly same for those with or without TD.

RESULTS Higher mean modal dose of olanzapine for patients with TD(23.65mg) versus those without TD(19.65mg).

DISCUSSION Not significant when corrected for multiple comparisions. Patients with TD had more severe psychopathology at base-line, perhaps requiring higher doses but this should apply for all treatment groups. Anticholinergic effects of olanzapine could have unmasked TD in some patients,adding them to TD group,but quietapine with highest rate of anticholinergic symptoms,didnt show similar dose effect. So the reasons for this are unclear

At 18 months, significant reduction in adjusted total AIMS scores

for all patients with TD at baseline. Similar reduction for all SGAs, no treatment differences noted. Mean SAS score decreased in TD patients but not significant BAS global score declined and was significant. Analyzing patients with TD, 55% met Schooler-Kane criteria at 2 consecutive visits post-baseline, 34% at all visits, 24% did not meet criteria for TD at any subsequent visit. No significance between treatment groups over % of TD patients meeting criteria for post-baseline. Only 7 % patients showed an increase in AIMS score of at least 50%, compared to 32% patients showed decrease of at least 50%. No significant association between use of first-generation antipsychotics prior to randomisation and TD during follow-up.

RESULTS Analyzing patients with TD, 55% met Schooler-Kane criteria at 2 consecutive visits post-baseline, 34% at all visits, 24% did not meet criteria for TD at any subsequent visit.

DISCUSSION Changes in TD were within the range of previous studies of FGAs and SGAs with similar % of pts showing increases, reduction or lack of diagnosable TD symptoms.

At 18 months, significant reduction in adjusted total AIMS scores for all patients with TD at baseline. Similar reduction for all SGAs, no treatment differences noted.

Limitation of study to show whether reductions in TD was due to remission or suppression as drugs cant be discontinued.

RESULTS Mean SAS(Simpson Angus Abbreviated scale) score decreased in TD patients but not significant. BAS global score declined and was significant

DISCUSSION Some investigators proposed suppression of TD is result of druginduced parkinsonism, this study found ratings of parkinsonism also declined during the study consistent that the antidyskinetic effect of antipsychotics is independent of their acute parkinsonian effects.

Post hoc analysis of CATIE study

CATIE was not designed to study the course and

correlates of TD No comprehensive measures of previous treatment history or onset of drug-induced movement disorders. Withdrawal dyskinesias (TD) may have occurred due to switching from prior antipsychotic to randomized CATIE treatment assignment in 1 month. Overcome by exclusion of 1-month visit from analysis. Training to rate movement disorders was not rigorousovercome by double-blind design.

No control over changes in antipsychotic doses

correlations between dose and long-term course of TD has not firmly established. High rate of discontinuations resulted in short duration of treatment and follow-up. But duration comparable to other studies. No attempt in dose reduction or withdrawal of drugs in trial, so cant say whether decreases in AIMS scores represented reversal or suppression of TD symptoms. Differences of cognition could have been affected by use of anticholinergics at baseline, other studies in CATIE found no interaction.

Longer duration of illness or greater age among TD pts

could have affect neurocognitive results-after covariate adjustment TD, pts still have significantly lower neurocognitive scores than non-TD pts. Primarily older patients and chronic course with long term exposure to antipsychotics-cant apply to other ages or stages of schizophrenia. Cant compare FGAs and SGAs as TD pts not assigned to perphenazine. Small no of pts in ziprasidone group limit conclusions Clozapine may be advantageous in treatment and dyskinesia outcomes but not included in this phase of study

TD may be associated with more severe psychopathology

and cognitive impairment in chronic schizophrenia. Patients with TD are equally likely to respond to treatment with any of these 4 SGAs compared to pts without TD except cognition Prognosis of TD was variable among individuals with majority of patients showing persistence or fluctuations between visits. Few patients showed significant increases in TD ratings during treatment. No significant differences between drug treatments on the course TD at dosages used in the trial.

TITLE Adequate , short, accurate, informative

AUTHORS The authors are from various universities from US. Most of the authors are consultants and has received grant/research support from drug companies which provided medications for the CATIE studies. Correspondence author Dr Caroff has been a consultant for Eli Lilly and has received research support from Pfizer and other drug companies. Approved by an institutional review board at each site

ABSTRACT: Brief and concise Fair and unbiased account of the paper INTRODUCTION AND REVIEW OF LITERATURE Brief and comprehensive Correct and necessary No important citations missing Has cited prior articles in favor as well as contrary to the results Has described reasons and need for the research project No explicit hypothesis.

AIMS AND OBJECTIVES Clear and unambiguous METHODOLOGY Place and period have been described Post hoc study analysis based on the CATIE Schizophrenia Trial Population representative of the general population

Sample size is large and sufficient.

Method of sample selection- random and double-

blind design blinding details ?? Probably no sample bias. Sample not homogenous, older and chronic course patients more. Socio-demographic as well as clinical variables studied Cases- no mention of co-morbid medical or neurological disorders that may affect TD. ? 12 patients randomly assigned to perphenazine were not assigned to others in phase 1b

Tools and Instruments suitable for investigation used.

But ?? neurocognitve tests used


Who administered? DSM IV criteria using SCID.

Procedure has been well described but details of some

missing in this journal although explained in previous CATIE study. Written informed consent was taken and research protocol passed by ethical committee Ethical

RESULTS Presented and described adequately Statistical methods suitable and appropriate, but discrepancy noted when different methods used. No obvious statistical manipulation

DISCUSSION Interpretation of data is justifiable & appropriate to study. Comparisons with previous studies & results for & against the study discussed. No important omissions Conclusions are reasonable

REFERENCES Adequate No important omissions


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