Supplemental Table 1 – Practical Clinical Trials in
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Supplemental Table 1 – Practical Clinical Trials in Psychopharmacology Published between January 2000 and October 2014 (N=30) Study Main question being addressed Sample (age in years) Setting Treatment Primary outcomes Treatment of dysthymia and minor depression in primary care Are paroxetine and problem-solving psychotherapy effective for primary care patients with dysthymia and minor depression in primary care? 415 adult patients with minor depression or dysthymia 4 primary care practices in the USA Paroxetine, placebo, or problem-solving psychotherapy for 11 weeks; doubleblind 10-item Hopkins Symptom Checklist Depression Scale and functional status Sertraline, exposure therapy, and combined treatment in social phobia Is sertraline effective in social phobia, with or without exposure therapy? 387 adult patients with social phobia 41 primary care practices in Norway or Sweden Clinical Global Impression and selfrated Social Phobia Scale 8 months A Randomized Trial Investigating SSRI Treatment (ARTIST) Do paroxetine, fluoxetine, and sertraline differ from one another in the treatment of depression in primary care? 573 adult patients with depressive disorder 37 primary care practices in the USA Sertraline, exposure therapy, or their combination, for 24 weeks; placebocontrolled; double-blind paroxetine, fluoxetine, or sertraline for 9 months; openlabel Efficacy and costeffectiveness of antidepressant Are fluoxetine and psychotherapy effective treatments 450 adults with depressive General medical outpatient Medical Outcome Study 36Item ShortForm Survey Mental Component Summary score Revised Clinical Interview Fluoxetine, placebo, or psychotherapy for Enrollment time 36 months Main findings Main source of funding Reference Paroxetine is effective in decreasing depressive symptoms and improving functioning. Smaller and inconsistent effect of psychotherapy Sertraline was effective, both with and without exposure therapy Hartford Foundation and MacArthur Foundation Williams et al. 200021 Pfizer Pharm. Blomhoff et al., 200122 8 months No difference Eli Lilly Pharm. Kroenke et al., 200123 6 months Fluoxetine, but not psycho- Wellcome Trust Patel et al., 200324 medication and psychotherapy in general health care International Suicide Prevention Trial (InterSePT) for depressed adults in general medical settings? Does clozapine reduce the risk of suicidality in schizophrenia? disorder clinics in India 980 adult patients with schizophrenia or schizoaffective disorder Rapid tranquillization of violent or agitated patients in psychiatric emergency setting Is there a difference between lorazepam and haloperidol/ promethazine given i.m. to control violent/agitated behavior? Are 2nd generation antipsychotics more effective than 1st generation antipsychotic? Haloperidol prophylaxis for elderly hip-surgery patients at risk for delirium Does pre- and postoperative haloperidol prevent delirium? Divalproex versus lithium for patients hospitalized for mania How does divalproex compare with lithium in controlling bipolar symptoms and medical costs for Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Schedule score 67 medical centers in 11 countries in Americas, Europe, and Africa. 6 months; doubleblind for pharmacotherapy Clozapine or olanzapine for 2 years; open-label, with masked reviewers of end points Suicide behavior, increased suicidal ideation and risk 11 months 200 adult patients with acute agitation, aggression or violent behavior 1,493 adult patients with schizophrenia Emergency services of general hospital in India Intramuscular lorazepam or haloperidol + promethazine; open-label Proportion tranquil or asleep 4 hours after injection 6 months 57 clinical sites in the USA Olanzapine, risperidone, quetiapine, ziprasidone, or perphenazine, for up to 18 months; double-blind All cause discontinuation 48 months 430 hipsurgery patients aged 70 and older at risk for delirium 201 patients with bipolar disordermanic episode General hospital in the NL Haloperidol 1.5 mg/d or placebo; double-blind Incidence of delirium 24 months 33 psychiatric practices in the USA Divalproex or lithium for one year; open-label Time free of manic or depressive symptoms 24 months therapy, was better than placebo Clozapine reduced the risk for suicidality compared with olanzapine No difference between treatments 74% of patients discontinued treatment; olanzapine was better than risperidone or quetiapine No difference in incidence of delirium (less severe delirium on haloperidol) No differences between treatments Novartis Pharm. Meltzer et al., 200325 Intramural academic grant and the Cochrane Schizophrenia Group Alexander et al., 200426 NIMH Lieberman et al., 200520 Hospital funds Kalisvaart et al., 200527 Abbott Pharm. Revicki et al., 200528 2 Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Broad Effectiveness Trial with Aripiprazole (BETA) Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CutLASS 1) Rapid tranquillisation in one year? To which antidepressant should patients be switched after unsuccessful SSRI treatment of major depression? How mirtazapine and nortriptyline compare as 3rd line anti-depressants following two consecutive failed medication treatments? Is aripiprazole effective for outpatients with schizophrenia or schizoaffective disorder? Are 2nd generation antipsychotics (other than clozapine) more effective than 1st generation antipsychotics? Is intramuscular haloperidol plus 727 adult patients with major depressive disorder 18 primary and 23 psychiatric care settings in the USA Bupropion, sertraline, or venlafaxine; openlabel Symptom remission (score <7 on the Hamilton Depression Rating Scale) Symptom remission (score <7 on the Hamilton Depression Rating Scale) Clinical Global Impression Improveme nt score 36 months The chance of remission is about 1 in 4 for any of the tested medications NIMH Rush et al., 200629 235 adult patients with major depressive disorder 18 primary and 23 psychiatric care settings in the USA Mirtazapine or nortriptyline for 14 weeks; openlabel 36 months Remission rate was 19.8% on nortriptyline and 12.3% on mirtazapine (not statistically different) Aripiprazole was effective NIMH Fava et al., 200630 1,599 adult outpatients with schizophrenia or schizoaffective disorder randomized to aripiprazole or other antipsychotic 227 adult patients with schizophrenia 291 general practices in the USA Aripiprazole or other antipsychotic, for 8 weeks; openlabel Bristol-Myers Squibb and Otsuka Pharm. Tandon et al., 200631 14 community psychiatric services in the UK A 1st or 2nd generation antipsychotic (other than clozapine), for 56 weeks; open-label Quality of Life Scale 30 months No advantage with 2nd generation antipsychotic was detected UK National Health Service Jones et al., 200632 316 adult patients with Emergency services of Intramuscular haloperidol + Proportion tranquil or 6 months Intramuscular haloperidol + Brazilian Research Huf et al., 48 months 3 psychiatric emergency settings in Brazil (TREC-Rio2) promethazine is superior to haloperidol alone Council 200733 10 months No difference Academic research fund Raveendran et al., 200734 Change in score on the Health of the Nation outcome scales for children and adolescents Investigator Assessment Questionnai re 48 months No advantage in adding CBT to SSRI UK National Health Service Goodyer et al., 200735 12 months Aripiprazole was more effective Bristol-Myers Squibb Pharm. Kerwin et al., 200736 Clinical Global ImpressionImproveme nt score All cause treatment discontinua- 24 months Aripiprazole was effective Bristol-Myers Squibb Co. and Otsuka Co. Wolf et al., 200737 4 years Patients assigned to 2nd generation AstraZeneca, Pfizer, SanofiAventis Kahn et al., 200838 promethazine better than haloperidol alone for managing agitated and violent behavior? Is intramuscular olanzapine better than haloperidol + promethazine for managing agitated and violent behavior? Is the combination of CBT and SSRI more effective than SSRI monotherapy for adolescent depression? mental illness and agitated or violent behavior general hospital in Brazil promethazine or haloperidol alone; open-label asleep by 20 minutes 300 adult patients with mental illness and agitated or violent behavior Emergency services of general hospital in India Intramuscular olanzapine or haloperidol + promethazine; open-label Proportion tranquil or asleep at 15 minutes and 240 minutes 208 patients (aged 11-17 years) with major depression 6 outpatient clinics in the UK SSRI +routine care or CBT +SSRI + routine care, for 12 weeks; openlabel Schizophrenia Trial of Aripiprazole (STAR) Is aripiprazole better tolerated than other 2nd generation antipsychotics? 555 adult patients with schizophrenia European Broad Effectiveness Trial with Aripiprazole (EU-BETA) Is aripiprazole effective for outpatients with schizophrenia? 833 adults with schizophrenia 98 community mental health centers in 12 European countries Practice settings in 14 European countries European First Episode Schizophrenia Trial Is a 2nd generation antipsychotic more effective than 498 adults with 1st episode Aripiprazole vs. standard of antipsychotic care (olanzapine, risperidone or quetiapine), for 26 weeks; open-label Aripiprazole vs. other antipsychotic, for 8 weeks; openlabel Amisulpiride, olanzapine, quetiapine, or Rapid tranquillisation in psychiatric emergency settings in India Adolescent Depression Antidepressant and Psychotherapy Trial (ADAPT) 50 sites in 12 European countries 4 (EUFEST) haloperidol? schizophrenia and Israel ziprasidone vs. haloperidol; openlabel tion Threshold for Antidepressant response study (THREAD) Is the addition of SSRI antidepressant to supportive care effective for patients with mild to moderate depression with somatic symptoms? Is Silexan, an Lavandula oil preparation, effective for subsyndromal anxiety? Is combined lithium and valproate better than either drug alone for relapse prevention in bipolar I? 220 adults diagnosed with new episode of depression 115 primary care practices in UK SSSRI + supportive care vs. supportive care alone, for 12 weeks; open-label Hamilton Depression Rating Scale score at week 12 3.5 years 221 adults with anxiety disorder not otherwise specified 27 general and psychiatric practices in Austria and Germany 41 sites in UK, France, Italy, and USA Lavadula 80 mg/day or placebo for 10 weeks; doubleblind Hamilton Anxiety Rating Scale 8 months Lithium, valproate, and their combination; open-label Mood episode requiring new intervention over 2 years 72 months Does the combination of two antidepressant results in better outcome of depression than monotherapy? Does ziprasidone increase non-suicide 665 adults with chronic or recurrent major depressive disorder 6 primary and 9 psychiatric care clinics in USA Remission rate at 3 and 7 months 1 year 18,154 adults with Psychiatric practices in Escitalopram, bupropion plus escitalopram, or venlafaxine plus mirtazapine, for 7 months; singleblind ziprasidone or olanzapine; open- 1 year nonsuicide 4 years Lavandula preparation in subsyndromal anxiety Bipolar Affective disorder: Lithium/ANtiConvu lsant Evaluation (BALANCE) Combining medications to enhance depression outcomes (COMED) Ziprasidone Observational 330 patients (age > 16 years) with bipolar I antipsychotics has lower discontinuation rate than haloperidol SSRI + supportive care is more effective UK National Health System Kendrick et al., 200939 Lavandula was more effective than placebo Schwabe Co. Kasper et al. 201040 Lithium, alone or in combination with valproate, is more effective than valproate alone in preventing relapse No superiority of combination over monotherapy Stanley Medical Research Institute and SanofiAventis BALANCE, 201041 NIMH Rush et al., 201142 No increase of non-suicide Pfizer Strom et al., 5 Study of Cardiac Outcomes (ZODIAC) mortality compared with olanzapine? schizophrenia USA and 17 other countries label mortality Comparison of Antipsychotics for Metabolic Problems (CAMP) Does switching from olanzapine, quetiapine, or risperidone to aripiprazole improve metabolic status in schizophrenia? Is sertraline or mirtazapine effective for depression in Alzheimer-type dementia? 215 adults with schizophrenia or schizoaffective disorder and metabolic risk factors 326 adults with possible or probable Alzheimer’s disease and depression 27 clinical sites of the Schizophreni a Trials Network in the USA Aripiprazole vs. olanzapine, quetiapine, or risperidone; openlabel with blinded raters Cholesterol and efficacy failure 38 months 9 clinical centers in UK Sertraline, mirtazapine, or placebo for 13 weeks; doubleblind Cornell scale for depression in dementia score 36 months Does the addition of ziprasidone to lithium or divalproex improve mania symptoms acutely? 680 adults with bipolar disorder I manic or mixed 47 clinical centers in the USA Young Mania Rating Scale Does lithium at moderate dose improve outcome in bipolar disorder? 283 Adults patients with bipolar disorder I or II 6 university clinics in the USA Ziprasidone, at low or high dose, or placebo, plus lithium or divalproex, for 3 weeks; doubleblind Lithium plus optimized personalized treatment (OPT) vs, OPT, for 6 months; openlabel Clinical Global Impression Scale for Bipolar Disorder; number of Health Technology Assessment Study of the Use of Antidepressants for Depression in Dementia (HTASADD) Adjunctive oral ziprasidone in bipolar disorder Lithium Treatment Moderate-Dose Use Study (LiTMUS) mortality on ziprasidone. Higher discontinuatio n and more hospitalization s on ziprasidone. Improved cholesterol and other metabolic indexes; no difference in efficacy failure 201143 Foundation for NIH, NIMH, and BristolMyers Squibb Stroup et al. 201144 No differences between active treatments, or placebo National Health Service Banerjee et al., 201145 33 months No benefit of adding ziprasidone Pfizer Sachs et al., 201246 48 months No advantage of lithium on primary outcomes NIMH Nierenberg et al., 201347 6 A Comparison of Long-acting Injectable Medications for Schizophrenia (ACLAIMS) Is paliperidone palmitate more effective than haloperidol decanoate in schizophrenia? 311 adults with schizophrenia or schizoaffective disorder 22 clinical sites in the USA Haloperidol decanoate vs. paliperidone palmitate, for up to 24 months; double-blind Comparison of long-acting vs. oral olanzapine in patients with schizophrenia at high risk of relapse Is long-acting olanzapine superior to oral olanzapine in maintaining patients on treatment? 524 adults with schizophrenia with 2 or more acute psychotic episodes in the past 2 years 49 clinics in the USA, South America, and Europe Olanzapine extended release 405 mg i.m. every 4 weeks vs. olanzapine 10 mg p.o. every day, for 24 months; openlabel necessary clinical adjustments Efficacy failure (hospitalizat ion, crisis, etc.) All-cause discontinua tion 28 months 40 months No difference in efficacy failure; more akathisia with haloperidol, and more weight gain and prolactin increase with paliperidone No difference in discontinuatio n NIMH McEvoy et al., 201448 Lilly Co. Detke et al., 201449 Legend: Adults: age 18 or older NIMH: National Institute of Mental Health SSRI: selective serotonin reuptake inhibitor 7
