Antipsychotics are the treatment of choice in managing schizophrenia and other psychotic disorders. Several major trials have been conducted examining the treatment of schizophrenia, including examining effectiveness, side effect profile, and pharmacoeconomic differences. These major trials have helped guide the way that antipsychotics are utilized.

  1. How do antipsychotics compare in regards to effectiveness?1-5
  2. Is there a clinical difference between typical antipsychotics and atypical antipsychotics?1
  3. How do antipsychotics differ as far as side effect profile?6
  4. Can antipsychotics be used for other ailments besides schizophrenia?7-8
  5. How does the antipsychotic selection affect quality of life?9-11
  6. Have any antipsychotics been shown to aid in decreasing suicidality?12
  7. How does schizophrenia impact life expectancy?

Cardiovascular risk factors and metabolic syndrome in people with established psychotic illnesses: baseline data from the IMPaCT randomized controlled trial. Gardner-Sood P, Lally J, Smith S, Atakan Z,

Ismail K, Greenwood KE, Keen A, O'Brien C, Onagbesan O, Fung C, Papanastasiou E, Eberhard J, Patel A, Ohlsen R, Stahl D, David A, Hopkins D, Murray RM, Gaughran F; IMPaCT team. Psychol Med. 2015;45(12):2619-29

Causes of the excess mortality of schizophrenia. Brown S, Inskip H, Barraclough B. Br J Psychiatry. 2000 Sep;177:212-7.


CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness)

  1. Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353(12):1209-23. [PubMed]
  2. Stroup TS, Lieberman JA, McEvoy JP, et al. Effectiveness of olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia after discontinuing perphenazine: a CATIE study. Am J Psychiatry. 2007;164(3):415-27. [PubMed]
  3. Stroup TS, Lieberman JA, McEvoy JP, et al. Effectiveness of olanzapine, quetiapine, risperidone, and ziprasidone in patients with chronic schizophrenia following discontinuation of a previous atypical antipsychotic. Am J Psychiatry. 2006;163(4):611-22. [PubMed]
  4. McEvoy JP, Lieberman JA, Stroup TS, et al. Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. Am J Psychiatry. 2006;163(4):600-10. [PubMed]
  5. Stroup TS, Lieberman JA, McEvoy JP, et al. Results of phase 3 of the CATIE schizophrenia trial. Schizophr Res. 2009;107(1):1-12. [PubMed]

CAFE (Metabolic Profiles of Second-Generation Antipsychotics in Early Psychosis)

  1. Patel JK, Buckley PF, Woolson S, et al. Metabolic profiles of second-generation antipsychotics in early psychosis: findings from the CAFE study. Schizophr Res. 2009 Jun;111(1-3):9-16. [PubMed]

CATIE-AD (Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer’s Disease)

  1. Schneider LS, Tariot PN, Dagerman KS, et al. Effectiveness of atypical antipsychotic drugs in patients with Alzheimer's disease. N Engl J Med. 2006;355(15):1525-38. [PubMed]

EUFEST (Effectiveness of Antipsychotics in First-Episode Schizophrenia and Schizophreniform Disorder)

  1. Kahn RS, Fleischhhacker WW, Boter H, et al. Effectiveness of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: an open randomised clinical trial. Lancet. 2008;371(9618):1085-97. [PubMed]

CUtLASS 1 (Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study)

  1. Jones PB, Barnes TR, Davies L, et al. Randomized controlled trial of the effect on Quality of Life of second- vs first-generation antipsychotic drugs in schizophrenia: Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1). Arch Gen Psychiatry. 2006 Oct;63(10):1079-87. [PubMed]

SOHO (Schizophrenia Outpatient Health Outcome)

  1. Knapp M, Windmeijer F, Brown J, et al. Cost-utility analysis of treatment with olanzapine compared with other antipsychotic treatments in patients with schizophrenia in the pan-European SOHO study. Pharmacoeconomics. 2008;26(4):341-58. [PubMed]
  2. Haro JM, Novick D, Suarez D, et al. Remission and relapse in the outpatient care of schizophrenia: three-year results from the Schizophrenia Outpatient Health Outcomes study. J Clin Psychopharmacol. 2006;26(6):571-8. [PubMed]

InterSePT (International Suicide Prevention Trial)

  1. Meltzer HY, Alphs L, Green AI, et al. Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT). Arch Gen Psychiatry. 2003;60(1):82-91. [PubMed]

Major Depressive Disorder (MDD)

Over the years, numerous classes of medications have been studied for the management of major depressive disorder, from MAOIs and TCAs to SSRIs, SNRIs, mirtazapine, bupropion, and atypical antipsychotics, among many others.

  1. What is a good first line strategy for managing MDD?1
  2. If my patient fails an SSRI, what should I try next?1-6
  3. What is the role of augmentation in managing MDD symptoms?5-7
  4. How does augmentation compare to switching agents?8


  1. Cipriani A, Furukawa TA, Salanti G, et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet. 2018;391(10128):1357-1366. [PubMed]

STAR*D (Sequenced Treatment Alternatives to Relieve Depression)

  1. Trivedi MH, Rush AJ, Wisniewski SR, et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry. 2006;163(1):28-40. [PubMed]
  2. Rush AJ, Trivedi MH, Wisniewski SR, et al. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N Engl J Med. 2006;354(12):1231-42.[PubMed]
  3. Fava M, Rush AJ, Wisniewski SR, et al. A comparison of mirtazapine and nortriptyline following two consecutive failed medication treatments for depressed outpatients: a STAR*D report. Am J Psychiatry. 2006;163(7):1161-72. [PubMed].
  4. McGrath PJ, Stewart JW, Fava M, et al. Tranylcypromine versus venlafaxine plus mirtazapine following three failed antidepressant medication trials for depression: a STAR*D report. Am J Psychiatry. 2006;163(9):1531-41. [PubMed]
  5. Trivedi MH, Fava M, Wisniewski SR, et al. Medication augmentation after the failure of SSRIs for depression. N Engl J Med. 2006;354(12):1243-52. [PubMed]
  6. Nierenberg AA, Fava M, Trivedi MH, et al. A comparison of lithium and T(3) augmentation following two failed medication treatments for depression: a STAR*D report. Am J Psychiatry. 2006;163(9):1519-30. [PubMed]

CO-MED (Combining Medications to Enhance Depression Outcomes)

  1. Rush AJ, Trivedi MH, Stewart JW, et al. Combining medications to enhance depression outcomes (CO-MED): acute and long-term outcomes of a single-blind randomized study. Am J Psychiatry. 2011;168(7):689-701. [PubMed]

VAST-D (VA Augmentation and Switching Treatments for Improving Depression Outcomes

  1. Mohamed S, Johnson GR, Chen P, et al. Effect of antidepressant switching vs augmentation on remission among patients with major depressive disorder unresponsive to antidepressant treatment: The VAST-D randomized clinical trial. JAMA. 2017;318(2):132-45. [PubMed]

Bipolar disorder

For years, lithium and the antiepileptics were the mainstay for treatment of bipolar disorder. In recent years, numerous antipsychotics have also been utilized.

  1. What is the evidence for combination of lithium and valproic acid in treatment of bipolar disorder?1
  2. What is the evidence for lithium or divalproex in treatment of mania in geriatric patients with bipolar disorder?2
  3. What is the evidence to support use of antipsychotics for management of bipolar disorder?3-7
  4. Should antidepressants be used to treat bipolar depression?6-9



  1. BALANCE investigators and collaborators, Geddes J, Goodwin GM , et al. Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomised open-label trial. Lancet. 2010;375(9712):385-95. [PubMed]


  1. Young RC, Mulsant BH, Sajatovic M, Gildengers AG, Gyulai L, AL Jurdi RK, et al. GERI-BD: A randomized double-blind controlled trial of lithium and divalproex in the treatment of mania in older patients with bipolar disorder. Am J Psychiatry. 2017;174(11):1086-93. [PubMed]

BOLDER (BipOLar DEpRession)

  1. Calabrese JR, Keck PE, Macfadden W, et al. A randomized, double-blind, placebo-controlled trial of quetiapine in the treatment of bipolar I or II depression. Am J Psychiatry. 2005;162(7):1351-60. [PubMed]

  2. Thase ME, Macfadden W, Weisler RH, et al. Efficacy of quetiapine monotherapy in bipolar I and II depression: a double-blind, placebo-controlled study (BOLDER II study). J Clin Psychopharmacol. 2006;26(6):600-9. [PubMed]


  1. Young AH, McElroy SL, Bauer M, et al. A double-blind, placebo-controlled study of quetiapine and lithium monotherapy in adults in the acute phase of bipolar depression (EMBOLDEN I). J Clin Psychiatry. 2010;71(2):150-62.  [PubMed]
  2. McElroy SL, Weisler RH, Chang W, et al. A double-blind, placebo-controlled study of quetiapine and paroxetine as monotherapy in adults with bipolar depression (EMBOLDEN II). J Clin Psychiatry. 2010;71(2):163-74. [PubMed]

STEP-BD (Systematic Treatment Enhancement Program for Bipolar Disorder)

  1. Nierenberg AA, Ostacher MJ, Calabrese JR, et al. Treatment-resistant bipolar depression: a STEP-BD equipoise randomized effectiveness trial of antidepressant augmentation with lamotrigine, inositol, or risperidone. Am J Psychiatry. 2006;163(2):210-6.[PubMed]
  2. Sachs GS, Nierenberg AA, Calabrese JR, et al. Effectiveness of adjunctive antidepressant treatment for bipolar depression. N Engl J Med. 2007;356(17):1711-22. [PubMed]
  3. Ghaemi SN, Ostacher MM, El-Mallakh RS, et al. Antidepressant discontinuation in bipolar depression: a Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) randomized clinical trial of long-term effectiveness and safety. J Clin Psychiatry. 2010;71(4):372-80. [PubMed]

Substance Abuse

Numerous pharmacologic regimens have been trialed for management of substance abuse, often with concomitant behavioral interventions.

  1. What is the evidence for combination of pharmacotherapy and behavioral intervention for managing symptoms of alcohol dependence?1


  1. Anton RF, O’Malley SS, Ciraulo DA, et al. Combined pharmacotherapies and behavioral interventions for alcohol dependence: the COMBINE study: a randomized controlled trial. JAMA. 2006;295(17):2003-17. [PubMed]

For opioid addition, what are viable treatments?

The SUMMIT trial: a field comparison of buprenorphine versus methadone maintenance treatment. Pinto H1, Maskrey V, Swift L, Rumball D, Wagle A, Holland R. J Subst Abuse Treat. 2010 Dec; 39(4):340-52


For pediatric patients with anxiety or depressive disorders, pharmacotherapy is often combined with cognitive behavioral therapy.

  1. What is the evidence for combination of pharmacotherapy and cognitive behavioral therapy for managing obsessive compulsive disorder in pediatric patients?1
  2. What is the evidence for combination of pharmacotherapy and cognitive behavioral therapy for managing depression in pediatric patients?2-3

Lithium in Paediatric Patients with Bipolar Disorder: Implications for Selection of Dosage Regimens via Population Pharmacokinetics/Pharmacodynamics. Landersdorfer CB, Findling RL, Frazier JA, Kafantaris V, Kirkpatrick CM. Clin Pharmacokinet. 2017 Jan;56(1):77-90.


POTS II (Pediatric OCD Treatment Study II)

  1. Franklin M, Sapyta J, Freeman J, et al. Cognitive behavior therapy augmentation of pharmacotherapy in pediatric obsessive-compulsive disorder: the Pediatric OCD Treatment Study II (POTS II) randomized controlled trial. JAMA. 2011;306(11):1224-32. [PubMed]

TADS (Treatment for Adolescents with Depression Study)

  1. March J, Silva S, Petrycki S, et al. Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression: Treatment for Adolescents with Depression Study (TADS) randomized controlled trial. JAMA. 2004;292(7):807-20. [PubMed]

TORDIA (Treatment of SSRI-Resistant Depression in Adolescents)

  1. Brent D, Emslie G, Clarke G, et al. Switching to another SSRI or to venlafaxine with or without cognitive behavioral therapy for adolescents with SSRI-resistant depression: the TORDIA randomized controlled trial. JAMA. 2008;299(8):901-13. [PubMed]