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Quantifying clinical relevance in treatments for psychiatric disorders Review article| Volume 33, ISSUE 12, PB62-B76, December 01, 2011

Communication of Potential Benefits and Harm to Patients and Payers in Psychiatry: A Review and Commentary

  • Renrong Wu
    Affiliations
    Department of Psychiatry, Mood and Anxiety Clinic in Mood Disorders Program, Case Western Reserve University School of Medicine, University Hospitals Case Medical Center, Cleveland, Ohio

    Institute of Mental Health of the Second Xiangya Hospital, Central South University, Changsha, Hunan, China
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  • David E. Kemp
    Affiliations
    Department of Psychiatry, Mood and Anxiety Clinic in Mood Disorders Program, Case Western Reserve University School of Medicine, University Hospitals Case Medical Center, Cleveland, Ohio
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  • Martha Sajatovic
    Affiliations
    Department of Psychiatry, Mood and Anxiety Clinic in Mood Disorders Program, Case Western Reserve University School of Medicine, University Hospitals Case Medical Center, Cleveland, Ohio
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  • Jingping Zhao
    Affiliations
    Institute of Mental Health of the Second Xiangya Hospital, Central South University, Changsha, Hunan, China
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  • Joseph R. Calabrese
    Affiliations
    Department of Psychiatry, Mood and Anxiety Clinic in Mood Disorders Program, Case Western Reserve University School of Medicine, University Hospitals Case Medical Center, Cleveland, Ohio
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  • Keming Gao
    Correspondence
    Address correspondence to: Keming Gao, MD, PhD, 10524 Euclid Avenue, 12th Floor, Cleveland, OH 44106
    Affiliations
    Department of Psychiatry, Mood and Anxiety Clinic in Mood Disorders Program, Case Western Reserve University School of Medicine, University Hospitals Case Medical Center, Cleveland, Ohio
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      Abstract

      Background

      Communicating potential benefits and harm to patients and payers is essential for high-quality care. However, there are no published guidelines or consensuses on how to communicate potential benefits and harm to patients and payers.

      Objective

      The goal of this review was to identify key elements for communication between clinicians, patients, and payers to achieve maximal benefits and minimal risk.

      Methods

      Literature published from January 1980 to July 2011 and cited on MEDLINE was searched using the terms communication, benefit, harm, effectiveness, cost, cost-effectiveness, psychiatry, bipolar disorder, schizophrenia, and major depressive disorder. Elements related to communicating benefits and/or harm to patients and payers were identified, with only key elements discussed in detail here.

      Results

      Evidence-based medicine, number needed to treat to benefit (NNTB) or harm (NNTH), and the likelihood of being helped or harmed (LHH) have been advocated as the basis for communication in all specialties of medicine. Phase-dependent communication of benefits and harm is novel, especially in patients with different phases of illness, such as bipolar disorder. Duration-dependent (short-term versus long-term) communication is essential for all psychiatric disorders to reduce the burden of relapse and adverse events with long-term treatment. For drugs with multiple therapeutic indications, a disease-dependent approach is crucial to maximize benefits and minimize harm. The exclusion of comorbid psychiatric disorders in pivotal efficacy trials affects their generalizability. Communicating cost (direct versus indirect) is an essential component in reducing health care expenditures. The results of available cost-effectiveness analyses of psychiatric pharmacotherapy have been inconsistent and/or contradictory.

      Conclusions

      Evidence-based communication of potential benefits and harm to patients and payers, using NNTB, NNTH, and LHH, should be the key principle that guides decision making. Phase-, duration-, and disease-dependent communication and evidence-based cost-saving principles can maximize benefit and reduce harm.

      Key words

      Introduction

      Like other specialties of medicine, in psychiatry, communication between health care professionals and patients and payers is essential for high-quality care. Unlike other specialties of medicine, in psychiatry, patients may carry a stigma that may sometimes cause them to be unwilling to receive proper treatment and/or to continue receiving treatment once they become asymptomatic. Psychiatric disorders such as schizophrenia, bipolar disorder, treatment-refractory major depressive disorder (MDD), and some anxiety disorders may be chronic and recurrent. Without maintenance treatment, relapse of these chronic illnesses may be inevitable.
      • Gaebel W.
      • Janner M.
      • Frommann N.
      • et al.
      First vs multiple episode schizophrenia: two-year outcome of intermittent and maintenance medication strategies.
      • Gaebel W.
      • Riesbeck M.
      • Wolwer W.
      • et al.
      Relapse prevention in first-episode schizophrenia—maintenance vs intermittent drug treatment with prodrome-based early intervention: results of a randomized controlled trial within the German Research Network on Schizophrenia.
      • Curson D.A.
      • Barnes T.R.
      • Bamber R.W.
      • et al.
      Long-term depot maintenance of chronic schizophrenic out-patients: the seven year follow-up of the Medical Research Council fluphenazine/placebo trial III. Relapse postponement or relapse prevention? The implications for long-term outcome.
      • Franks M.A.
      • Macritchie K.A.
      • Mahmood T.
      • et al.
      Bouncing back: is the bipolar rebound phenomenon peculiar to lithium? A retrospective naturalistic study.
      • Viguera A.C.
      • Whitfield T.
      • Baldessarini R.J.
      • et al.
      Risk of recurrence in women with bipolar disorder during pregnancy: prospective study of mood stabilizer discontinuation.
      • Biel M.G.
      • Peselow E.
      • Mulcare L.
      • et al.
      Continuation versus discontinuation of lithium in recurrent bipolar illness: a naturalistic study.
      • Kaymaz N.
      • van Os J.
      • Loonen A.J.
      • et al.
      Evidence that patients with single versus recurrent depressive episodes are differentially sensitive to treatment discontinuation: a meta-analysis of placebo-controlled randomized trials.
      • Baldessarini R.J.
      • Tondo L.
      • Ghiani C.
      • et al.
      Illness risk following rapid versus gradual discontinuation of antidepressants.
      • Frank E.
      • Perel J.M.
      • Mallinger A.G.
      • et al.
      Relationship of pharmacologic compliance to long-term prophylaxis in recurrent depression.
      The consequences of relapse may increase the burden on not only patients' health but also society.
      • Ascher-Svanum H.
      • Zhu B.
      • Faries D.E.
      • et al.
      The cost of relapse and the predictors of relapse in the treatment of schizophrenia.
      • Bagalman E.
      • Yu-Isenberg K.S.
      • Durden E.
      • et al.
      Indirect costs associated with nonadherence to treatment for bipolar disorder.
      • Hong J.
      • Windmeijer F.
      • Novick D.
      • et al.
      The cost of relapse in patients with schizophrenia in the European SOHO (Schizophrenia Outpatient Health Outcomes) study.
      Disparity of health coverage for patients with psychiatric illness remains a worldwide problem. Restrictions on accessing certain medications or services imposed by payers are common. Consequently, patients with psychiatric illness may be unable to receive proper treatment or may be required to making unnecessary changes. Subsequently, the risk for nonadherence and relapse and their ensuing costs may increase.
      • Bagalman E.
      • Yu-Isenberg K.S.
      • Durden E.
      • et al.
      Indirect costs associated with nonadherence to treatment for bipolar disorder.
      • Zhang Y.
      • Adams A.S.
      • Ross-Degnan D.
      • et al.
      Effects of prior authorization on medication discontinuation among Medicaid beneficiaries with bipolar disorder.
      • Gibson T.B.
      • Jing Y.
      • Kim E.
      • Bagalman E.
      • et al.
      Cost-sharing effects on adherence and persistence for second-generation antipsychotics in commercially insured patients.
      Clearly, it is essential to communicate the potential benefit versus harm to patients and payers of each intervention or policy to provide the best care for each patient. Although communication with patients is a basic component of training for every health care professional, there are no published guidelines or consensuses on how to communicate effectively with patients and payers, especially with reference to communication of potential benefits and harm. Undoubtedly, improved communication may help patients to comply with their treatment and to secure needed resources. This article proposes some key elements to help clinicians to communicate with patients and payers.

      Methods

      Literature published from January 1980 to July 2011 and cited on MEDLINE was searched using the terms communication, benefit, harm, effectiveness, cost, cost-effectiveness, psychiatry, bipolar disorder, schizophrenia, and major depressive disorder. Elements related to communicating benefits and/or harm to patients and payers were identified, with only key elements discussed in detail here.

      Results

      Communication of Evidence-Based Medicine

      A MEDLINE search with different combinations of key words uncovered more than one thousand abstracts, 105 articles were carefully examined and included for this review. Clinical experience is important in patient care, but evidence-based practice and good communication with patients and payers is essential for providing the best care for patients. Evidence-based medicine is defined as the integration of clinical expertise and the best external evidence,
      • Sackett D.L.
      • Rosenberg W.M.
      • Gray J.A.
      • et al.
      Evidence based medicine: what it is and what it isn't.
      with the key being “best” evidence. Even now, it is difficult to define what constitutes “best” evidence. Randomized, controlled trials, especially double-blind trials, were long believed to provide the best evidence, but researchers have now attempted to grade the quality of evidence using classification systems.
      • Sackett D.L.
      • Rosenberg W.M.
      • Gray J.A.
      • et al.
      Evidence based medicine: what it is and what it isn't.
      The Grading of Recommendation Assessment Development and Evaluation Working Group has emphasized the importance of grading the quality of evidence among randomized controlled trials.
      • Guyatt G.H.
      • Oxman A.D.
      • Kunz R.
      • et al.
      What is “quality of evidence” and why is it important to clinicians?.
      • Balshem H.
      • Helfand M.
      • Schunemann H.J.
      • et al.
      GRADE guidelines: 3 Rating the quality of evidence.
      Findings from systematic reviews and meta-analyses based on randomized controlled trials have also been proposed as the best evidence, followed by randomized controlled trials.
      • Guyatt G.H.
      • Oxman A.D.
      • Kunz R.
      • et al.
      What is “quality of evidence” and why is it important to clinicians?.
      • Balshem H.
      • Helfand M.
      • Schunemann H.J.
      • et al.
      GRADE guidelines: 3 Rating the quality of evidence.
      However, systematic reviews and meta-analyses commonly lag behind randomized controlled trials and other sources of new scientific discoveries. It is important for clinicians and payers to have their own updated best evidence–based information. A detailed discussion on how to find evidence-based information is beyond the scope of this review. A step-by-step strategy for identifying evidence-based information has been proposed.
      • Virgilio R.F.
      • Chiapa A.L.
      • Palmarozzi E.A.
      Evidence-based medicine, part 1 An introduction to creating an answerable question and searching the evidence.

      Communication of Efficacy

      Conventional Efficacy Measures

      Although the data from randomized, double-blinded, controlled trials may provide the best evidence, they rarely can directly be used to communicate with patients or payers. Commonly, the efficacy and tolerability of a psychotropic drug are determined through randomized, double-blind, placebo-controlled trials, with efficacy measured through standardized rating scales, such as the Hamilton Depression Rating Scale (HDRS) or the Montgomery-Åsberg Depression Rating Scale (MADRS) for depression, the Young Mania Rating Scale (YMRS) for mania, and the Positive and Negative Syndrome Scale (PANSS) for psychosis. For maintenance studies, the primary outcomes are commonly the difference in time to relapse/intervention between studied treatments and their controls.
      • Gao K.
      • Kemp D.E.
      • Calabrese J.R.
      Pharmacological treatment of the maintenance phase of bipolar depression: focus on relapse prevention studies and the impact of design on generalizability.
      Overall changes in rating scales have little use in clinical practice and policy making. First, the use of rating scales to measure symptom severity has not been routinely evaluated in clinical care settings, although they can provide useful information. Second, it is often difficult for patients to understand the meaning of, for example, a 20-point reduction on the HDRS or a 15-point reduction on the YMRS. Third, the rate of response (eg, ≥50% reduction in depression symptoms or manic symptoms, ≥30% reduction in psychotic symptoms in schizophrenia), a commonly used secondary outcome, also has limited clinical relevance. For instance, if a patient has a MADRS total score of 40 points at baseline and that score is reduced to 20 points at the end of study, the patient will meet the criteria for response. However, a MADRS total score of 20 points suggests that the patient is still moderately depressed. Without interpreting scores in the appropriate context, it may be difficult for payers to understand the meaning of these changes. Therefore, it is important for clinicians to use simple and easy ways to communicate efficacy to patients and payers.

      Number Needed to Treat

      The number needed to treat (NNT) is a more clinically relevant way to communicate efficacy to patients and payers, although there are other ways to present differences between groups, such as relative risk, relative risk reduction, absolute risk reduction, and odds ratio.
      • McQuay H.J.
      • Moore R.A.
      Using numerical results from systematic reviews in clinical practice.
      The NNT has the crucial advantage of direct applicability to clinical practice. It is simple to use and can be easily understood by patients and payers. The additional advantage of NNT is that it can be applied to any binary or dichotomous beneficial outcome or adverse event.
      • Karagianis J.
      • Rosenbluth M.
      • Tohen M.
      • et al.
      Reviewing CATIE for clinicians: balancing benefit and risk using evidence-based medicine tools.
      • Wang Z.
      • Kemp D.E.
      • Chan P.K.
      • et al.
      Comparisons of the tolerability and sensitivity of quetiapine-XR in the acute treatment of schizophrenia, bipolar mania, bipolar depression, major depressive disorder, and generalized anxiety disorder.
      • Gao K.
      • Ganocy S.J.
      • Gajwani P.
      • et al.
      A review of sensitivity and tolerability of antipsychotics in patients with bipolar disorder or schizophrenia: focus on somnolence.
      • Gao K.
      • Kemp D.E.
      • Fein E.
      • et al.
      Number needed to treat to harm for discontinuation due to adverse events in the treatment of bipolar depression, major depressive disorder, and generalized anxiety disorder with atypical antipsychotics.
      For continuous data, NNT can be calculated after a threshold is set. For these reasons, NNT has been advocated for use in systematic reviews.
      • McQuay H.J.
      • Moore R.A.
      Using numerical results from systematic reviews in clinical practice.
      • Wang Z.
      • Kemp D.E.
      • Chan P.K.
      • et al.
      Comparisons of the tolerability and sensitivity of quetiapine-XR in the acute treatment of schizophrenia, bipolar mania, bipolar depression, major depressive disorder, and generalized anxiety disorder.

      Number Needed to Treat to Benefit

      Based on the focus of the study outcome, benefit or harm, of a treatment relative to its comparator (placebo or an active treatment), NNT is subclassified as number needed to treat to benefit (NNTB) and number needed to treat to harm (NNTH). In the literature, NNTB is also commonly referred to as NNT, and NNTH as NNH.
      • Citrome L.
      Number needed to treat: what it is and what it isn't, and why every clinician should know how to calculate it.
      The NNTB is the reciprocal of the absolute risk reduction of a treatment relative to its control (placebo or an active treatment) (NNTB = 1/[Events in the study group – Events in the control group]).
      • Altman D.G.
      Confidence intervals for the number needed to treat.
      The event can be response, remission, or relapse. Clinically, the NNTB is the number of patients who would be expected to be treated with a study drug to result in 1 more success (response or remission) than if the same number were treated with the control.
      • Wang Z.
      • Kemp D.E.
      • Chan P.K.
      • et al.
      Comparisons of the tolerability and sensitivity of quetiapine-XR in the acute treatment of schizophrenia, bipolar mania, bipolar depression, major depressive disorder, and generalized anxiety disorder.
      The NNTB conveys to clinicians, patients, and payers not only the magnitude of an effect size of a studied drug compared with that of a control but also the effect sizes between multiple drugs or the same drug at different doses. To demonstrate this function of NNTB, quetiapine extended release (QTP-XR) is used as an example. QTP is a multifunctional atypical antipsychotic. The US Food and Drug Administration (FDA) has approved the use of QTP-XR monotherapy for the acute treatment of schizophrenia, mania, and bipolar depression, and as adjunctive therapy to antidepressants for the acute treatment of failed response to initial antidepressant treatment. The FDA has also approved the use of aripiprazole and olanzapine monotherapy for the acute treatment of schizophrenia and mania, and as adjunctive therapy to antidepressants for the acute treatment of failed response to initial antidepressant treatment, but it did not approve these 2 medications for use as monotherapy for bipolar depression. Meanwhile, Only QTP-XR studies used fixed-dosing schedules. Therefore, using the results from QTP-XR studies may provide the least-biased comparisons of NNTB and NNTH in different psychiatric conditions at the same dose or in the same psychiatric condition at different doses.
      As shown in Table I,
      • Kahn R.S.
      • Schulz S.C.
      • Palazov V.D.
      • et al.
      Efficacy and tolerability of once-daily extended release quetiapine fumarate in acute schizophrenia: a randomized, double-blind, placebo-controlled study.
      • Cutler A.J.
      • Montgomery S.A.
      • Feifel D.
      • et al.
      Extended release quetiapine fumarate monotherapy in major depressive disorder: a placebo- and duloxetine-controlled study.
      • Weisler R.
      • Joyce M.
      • McGill L.
      • et al.
      Extended release quetiapine fumarate monotherapy for major depressive disorder: results of a double-blind, randomized, placebo-controlled study.
      • Cutler A.J.
      • Datto C.
      • Nordenhem A.
      • et al.
      Extended-Release Quetiapine as Monotherapy for the Treatment of Adults With Acute Mania: A Randomized, Double-Blind, 3-Week Trial.
      • Suppes T.
      • Datto C.
      • Minkwitz M.
      • et al.
      Effectiveness of the extended release formulation of quetiapine as monotherapy for the treatment of acute bipolar depression.
      • Bauer M.
      • Pretorius H.W.
      • Constant E.L.
      • et al.
      Extended-release quetiapine as adjunct to an antidepressant in patients with major depressive disorder: results of a randomized, placebo-controlled, double-blind study.
      in the acute treatment of schizophrenia with QTP-XR,
      • Kahn R.S.
      • Schulz S.C.
      • Palazov V.D.
      • et al.
      Efficacy and tolerability of once-daily extended release quetiapine fumarate in acute schizophrenia: a randomized, double-blind, placebo-controlled study.
      the NNTB was smaller for the 600-mg/d dose compared with the 400-mg/d dose (3 vs 7, respectively), suggesting that 600 mg/d was more effective than 400 mg/d compared with placebo. Similarly, in the treatment of MDD with QTP-XR,
      • Cutler A.J.
      • Montgomery S.A.
      • Feifel D.
      • et al.
      Extended release quetiapine fumarate monotherapy in major depressive disorder: a placebo- and duloxetine-controlled study.
      • Weisler R.
      • Joyce M.
      • McGill L.
      • et al.
      Extended release quetiapine fumarate monotherapy for major depressive disorder: results of a double-blind, randomized, placebo-controlled study.
      150 mg/d was more effective than 50 mg/d, with an NNTB of 5 versus 10.
      Table INumber needed to treat to benefit (NNTB) and number needed to treat to harm (NNTH) for response with the use of quetiapine extended release (QTP-XR) in the treatment of schizophrenia, mania, bipolar depression, and major depressive disorder.
      Diagnosis/Study/Treatment ArmsResponse RateNNTB, Mean (95% CI)DAE RateNNTH, Mean (95% CI)
      Schizophrenia
       Kahn et al (2007)
      • Kahn R.S.
      • Schulz S.C.
      • Palazov V.D.
      • et al.
      Efficacy and tolerability of once-daily extended release quetiapine fumarate in acute schizophrenia: a randomized, double-blind, placebo-controlled study.
      (6 Wk)
        QTP-XR 400 mg/d49/1117 (4–90)6/113N/A
        QTP-XR 600 mg/d67/1113 (2–6)3/113N/A
        QTP-XR 800 mg/d66/1174 (3–8)3/121N/A
        Placebo35/1153/118
      MDD
       Cutler et al (2009)
      • Cutler A.J.
      • Montgomery S.A.
      • Feifel D.
      • et al.
      Extended release quetiapine fumarate monotherapy in major depressive disorder: a placebo- and duloxetine-controlled study.
      and Weisler et al (2009)
      • Weisler R.
      • Joyce M.
      • McGill L.
      • et al.
      Extended release quetiapine fumarate monotherapy for major depressive disorder: results of a double-blind, randomized, placebo-controlled study.
      (6 Wk)
        QTP-XR 50 mg/d76/17810 (5–112)15/181N/A
        QTP-XR 150 mg/d178/3345 (4–8)55/3289 (19–19)
        QTP-XR 300 mg/d172/3376 (4–9)57/3319 (6–15)
        Duloxetine 60 mg/d67/1417 (4–21)20/14913 (7–50)
        Placebo109/33020/338
      Mania
       Vieta et al (2010)
      • Cutler A.J.
      • Datto C.
      • Nordenhem A.
      • et al.
      Extended-Release Quetiapine as Monotherapy for the Treatment of Adults With Acute Mania: A Randomized, Double-Blind, 3-Week Trial.
      (3 Wk)
        QTP-XR 400–800 mg/d82/1495 (3–9)4/155N/A
        Placebo53/15912/161
      Bipolar disorder
       Suppes et al (2010)
      • Suppes T.
      • Datto C.
      • Minkwitz M.
      • et al.
      Effectiveness of the extended release formulation of quetiapine as monotherapy for the treatment of acute bipolar depression.
      (8 Wk)
        QTP-XR 300 mg/d87/1334 (3–10)17/1399 (6–20)
        Placebo59/1372/138
      Refractory MDD
       Bauer et al (2009)
      • Bauer M.
      • Pretorius H.W.
      • Constant E.L.
      • et al.
      Extended-release quetiapine as adjunct to an antidepressant in patients with major depressive disorder: results of a randomized, placebo-controlled, double-blind study.
      (6 Wk)
        QTP-XR 150 mg/d92/166N/A27/31515 (10–21)
        QTP-XR 300 mg/d179/3078 (5–24)46/3118 (6–11)
        Placebo140/3036/312
      DAE = discontinuation due to adverse events; MDD = major depressive disorder; N/A = not available due to no significant difference vs placebo.
      Although the concept of the NNTB is straightforward, clinicians should keep in mind that the quality of evidence from randomized, controlled trials might be compromised by the design and the conduct of the study.

      Number Needed to Treat to Harm

      The NNTH is the reciprocal of the absolute risk increase relative to its control (NNTH = 1/[Adverse events in a study group – Adverse events in the control group]).
      • Altman D.G.
      Confidence intervals for the number needed to treat.
      Clinically, NNTH is the number of patients that would be expected to be treated with a study drug to have 1 more failure or adverse event than if the same number were treated with a control. Tolerability may be measured using the rate of discontinuation due to adverse events (DAEs) or the rates of events such as somnolence or clinically significant weight gain.
      • Karagianis J.
      • Rosenbluth M.
      • Tohen M.
      • et al.
      Reviewing CATIE for clinicians: balancing benefit and risk using evidence-based medicine tools.
      • Wang Z.
      • Kemp D.E.
      • Chan P.K.
      • et al.
      Comparisons of the tolerability and sensitivity of quetiapine-XR in the acute treatment of schizophrenia, bipolar mania, bipolar depression, major depressive disorder, and generalized anxiety disorder.
      • Gao K.
      • Ganocy S.J.
      • Gajwani P.
      • et al.
      A review of sensitivity and tolerability of antipsychotics in patients with bipolar disorder or schizophrenia: focus on somnolence.
      • Gao K.
      • Kemp D.E.
      • Fein E.
      • et al.
      Number needed to treat to harm for discontinuation due to adverse events in the treatment of bipolar depression, major depressive disorder, and generalized anxiety disorder with atypical antipsychotics.
      The NNTH can be used for easily informing clinicians, patients, and payers about the differences in adverse-event risks with a drug compared to a control, and for comparing adverse-event risks among multiple drugs or different doses of the same drug.
      • Karagianis J.
      • Rosenbluth M.
      • Tohen M.
      • et al.
      Reviewing CATIE for clinicians: balancing benefit and risk using evidence-based medicine tools.
      • Wang Z.
      • Kemp D.E.
      • Chan P.K.
      • et al.
      Comparisons of the tolerability and sensitivity of quetiapine-XR in the acute treatment of schizophrenia, bipolar mania, bipolar depression, major depressive disorder, and generalized anxiety disorder.
      • Gao K.
      • Ganocy S.J.
      • Gajwani P.
      • et al.
      A review of sensitivity and tolerability of antipsychotics in patients with bipolar disorder or schizophrenia: focus on somnolence.
      • Gao K.
      • Kemp D.E.
      • Fein E.
      • et al.
      Number needed to treat to harm for discontinuation due to adverse events in the treatment of bipolar depression, major depressive disorder, and generalized anxiety disorder with atypical antipsychotics.
      For instance, in the acute treatment of schizophrenia,
      • Kahn R.S.
      • Schulz S.C.
      • Palazov V.D.
      • et al.
      Efficacy and tolerability of once-daily extended release quetiapine fumarate in acute schizophrenia: a randomized, double-blind, placebo-controlled study.
      bipolar mania,
      • Cutler A.J.
      • Datto C.
      • Nordenhem A.
      • et al.
      Extended-Release Quetiapine as Monotherapy for the Treatment of Adults With Acute Mania: A Randomized, Double-Blind, 3-Week Trial.
      bipolar depression,
      • Suppes T.
      • Datto C.
      • Minkwitz M.
      • et al.
      Effectiveness of the extended release formulation of quetiapine as monotherapy for the treatment of acute bipolar depression.
      and MDD,
      • Cutler A.J.
      • Montgomery S.A.
      • Feifel D.
      • et al.
      Extended release quetiapine fumarate monotherapy in major depressive disorder: a placebo- and duloxetine-controlled study.
      • Bauer M.
      • Pretorius H.W.
      • Constant E.L.
      • et al.
      Extended-release quetiapine as adjunct to an antidepressant in patients with major depressive disorder: results of a randomized, placebo-controlled, double-blind study.
      there were no significant differences between QTP-XR and placebo in the risk for DAEs in schizophrenia and bipolar mania, but there were significantly increased risks for DAEs in bipolar depression and MDD, with NNTHs ranging from 8 to 15 (Table I).
      In contrast to efficacy (benefit), the tolerability (harm) of a study drug is not typically selected as a primary study outcome, although 1 study used a combined efficacy/tolerability (effectiveness) measure as a primary outcome.
      • Lieberman J.A.
      • Stroup T.S.
      • McEvoy J.P.
      • et al.
      Effectiveness of antipsychotic drugs in patients with chronic schizophrenia.
      Tolerability data are commonly reported as the prevalence of DAEs; severe adverse events; or specific adverse events, such as somnolence, sedation, and weight gain. Because studies are generally not powered to evaluate tolerability as a primary outcome measure, the difference in any tolerability measure between a studied drug and its control may not be entirely accurate. For example, in a post-hoc analysis of patients with rapid cycling bipolar disorder, patients with a recent substance use disorder tolerated lithium + divalproex better than did those without a recent substance use disorder.
      • Gao K.
      • Kemp D.E.
      • Wang Z.
      • et al.
      Predictors of non-stabilization during the combination therapy of lithium and Divalproex in rapid cycling bipolar disorder: a post-hoc analysis of two studies.
      During treatment with lithium + divalproex, patients with rapid cycling bipolar disorder and a recent substance use disorder had significantly increased levels of thyroid stimulating hormone compared with those without a recent substance use disorder.
      • Gao K.
      • Kemp D.E.
      • Calabrese J.R.
      Recent substance use disorder, not generalized anxiety disorder, intensifies lithium-induced THS increase in rapid-cycling bipolar disorder.
      However, in all pivotal efficacy studies irrespective of diagnosis, patients with a recent history of a substance use disorder are excluded. Therefore, the tolerability data from pivotal studies are not always generalizable to routine clinical practice.

      Likelihood of Being Helped or Harmed

      The NNTB and NNTH can easily help clinicians, patients, and payers to determine the likelihood of being helped or harmed (LHH) by a treatment.
      • Wang Z.
      • Kemp D.E.
      • Chan P.K.
      • et al.
      Comparisons of the tolerability and sensitivity of quetiapine-XR in the acute treatment of schizophrenia, bipolar mania, bipolar depression, major depressive disorder, and generalized anxiety disorder.
      • McAlister F.A.
      • Straus S.E.
      • Guyatt G.H.
      • Haynes R.B.
      Evidence-Based Medicine Working Group
      Users' guides to the medical literature Integrating research evidence with the care of the individual patient.
      • Citrome L.
      • Kantrowitz J.
      Antipsychotics for the treatment of schizophrenia: likelihood to be helped or harmed, understanding proximal and distal benefits and risks.
      The LHH is usually expressed as an aggregate ratio of 1/NNTB (absolute risk reduction):1/NNTH (absolute risk increase).
      • McAlister F.A.
      • Straus S.E.
      • Guyatt G.H.
      • Haynes R.B.
      Evidence-Based Medicine Working Group
      Users' guides to the medical literature Integrating research evidence with the care of the individual patient.
      If the ratio is >1, then the likelihood is greater that a patient would be helped than harmed. As shown in Table I, if patients take QTP-XR for the acute treatment of schizophrenia or mania, they are more likely to be helped because the risk for DAEs did not significantly differ between QTP-XR and placebo. On the other hand, if patients take QTP-XR for bipolar depression or MDD, the LHH is more dependent on the dose administered. At a dose of 300 mg/d for bipolar depression, the likelihood of being helped is greater than the likelihood of being harmed, with a NNTB of 4 versus a NNTH of 9. At a QTP-XR dose of 150 mg/d for adjunctive therapy to antidepressants in the treatment of refractory MDD, the likelihood of being harmed is greater than the likelihood of being helped, with a NNTH of 15 versus no significant difference in benefit between QTP-XR and placebo. In contrast, at a dose of 300 mg/d in treatment-refractory MDD, the likelihood of being helped is equal to the likelihood of being harmed, with a NNTB and a NNTH of 8.

      Communication Based on Phase of Illness

      The majority of psychiatric patients will oscillate between at least 2 phases of illness, acute and euthymic. Most patients with BD will experience at least 3 phases—acute depression, acute mania/hypomania, and euthymia. Communication with patients and payers should emphasize differences in potential benefits and harm based on different phases of illness. Previously published analyses by the authors have shown that patients with mania had better tolerability and lower sensitivity to antipsychotics than did those in a depressive phase (Table I),
      • Wang Z.
      • Kemp D.E.
      • Chan P.K.
      • et al.
      Comparisons of the tolerability and sensitivity of quetiapine-XR in the acute treatment of schizophrenia, bipolar mania, bipolar depression, major depressive disorder, and generalized anxiety disorder.
      • Gao K.
      • Ganocy S.J.
      • Gajwani P.
      • et al.
      A review of sensitivity and tolerability of antipsychotics in patients with bipolar disorder or schizophrenia: focus on somnolence.
      suggesting that during a manic phase of illness, an emphasis should be placed on efficacy instead of tolerability so that a high dose of medication can be used and a faster titration schedule can be implemented. This practice might improve manic symptoms faster without compromising tolerability. In contrast, when treating patients in a depressive phase, efficacy and tolerability should be equally emphasized to reduce DAEs and specific adverse events.
      • Wang Z.
      • Kemp D.E.
      • Chan P.K.
      • et al.
      Comparisons of the tolerability and sensitivity of quetiapine-XR in the acute treatment of schizophrenia, bipolar mania, bipolar depression, major depressive disorder, and generalized anxiety disorder.
      • Gao K.
      • Ganocy S.J.
      • Gajwani P.
      • et al.
      A review of sensitivity and tolerability of antipsychotics in patients with bipolar disorder or schizophrenia: focus on somnolence.
      Thus, it is reasonable to start at a lower dose of a medication and employ a titration schedule that is slower than that recommended by the manufacturer.
      So far, almost all intervention studies, pharmacologic or psychological, have enrolled patients in the acute phase regardless of diagnosis. A few drugs have been studied in patients who were euthymic or relatively stable.
      • Gao K.
      • Kemp D.E.
      • Calabrese J.R.
      Pharmacological treatment of the maintenance phase of bipolar depression: focus on relapse prevention studies and the impact of design on generalizability.
      • Hirsch S.R.
      • Kissling W.
      • Bauml J.
      • et al.
      A 28-week comparison of ziprasidone and haloperidol in outpatients with stable schizophrenia.
      Therefore, the acute efficacy and tolerability of psychotropic drugs in euthymic patients are yet to be fully determined through prophylactic maintenance designs.
      • Gao K.
      • Kemp D.E.
      • Calabrese J.R.
      Pharmacological treatment of the maintenance phase of bipolar depression: focus on relapse prevention studies and the impact of design on generalizability.

      Communication Based on Duration of Treatment

      Communicating benefits and harm to patients and payers should also be dependent on the duration of treatment. Short-term priorities include efficacy and management of acute adverse events. For example, the acute adverse events from antipsychotics such as quetiapine and olanzapine in bipolar depression include dry mouth, somnolence, and sedation. Somnolence/sedation is a common cause of DAEs.
      • Wang Z.
      • Kemp D.E.
      • Chan P.K.
      • et al.
      Comparisons of the tolerability and sensitivity of quetiapine-XR in the acute treatment of schizophrenia, bipolar mania, bipolar depression, major depressive disorder, and generalized anxiety disorder.
      • Gao K.
      • Ganocy S.J.
      • Gajwani P.
      • et al.
      A review of sensitivity and tolerability of antipsychotics in patients with bipolar disorder or schizophrenia: focus on somnolence.
      • Gao K.
      • Kemp D.E.
      • Fein E.
      • et al.
      Number needed to treat to harm for discontinuation due to adverse events in the treatment of bipolar depression, major depressive disorder, and generalized anxiety disorder with atypical antipsychotics.
      • Calabrese J.R.
      • Keck Jr, P.E.
      • Macfadden W.
      • et al.
      A randomized, double-blind, placebo-controlled trial of quetiapine in the treatment of bipolar I or II depression.
      • Tohen M.
      • Vieta E.
      • Calabrese J.
      • et al.
      Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression.
      Helping patients to expect and deal with adverse events that are likely to be transient (as is often the case with drug titration–related sedation), may help them to adhere to treatment during the initial phase. Long-term priorities should be focused on relapse prevention and long-term adverse events, such as weight gain and metabolic changes from antipsychotics.
      • Tohen M.
      • Calabrese J.R.
      • Sachs G.S.
      • et al.
      Randomized, placebo-controlled trial of olanzapine as maintenance therapy in patients with bipolar I disorder responding to acute treatment with olanzapine.
      • Wu R.R.
      • Zhao J.P.
      • Jin H.
      • et al.
      Lifestyle intervention and metformin for treatment of antipsychotic-induced weight gain: a randomized controlled trial.
      Patients with bipolar disorder may tolerate higher dosages of medications better when they are manic than when they are depressed.
      • Wang Z.
      • Kemp D.E.
      • Chan P.K.
      • et al.
      Comparisons of the tolerability and sensitivity of quetiapine-XR in the acute treatment of schizophrenia, bipolar mania, bipolar depression, major depressive disorder, and generalized anxiety disorder.
      • Gao K.
      • Ganocy S.J.
      • Gajwani P.
      • et al.
      A review of sensitivity and tolerability of antipsychotics in patients with bipolar disorder or schizophrenia: focus on somnolence.
      Thus, dosage adjustment of medications initiated in an acute phase may be necessary if the medications are needed for long-term use. Although it remains unclear whether patients with schizophrenia, MDD, or anxiety disorders have a different tolerability from an acute phase to a stable phase, dose adjustments according to treatment response and adverse events have been reported in outpatients with schizophrenia.
      • Suarez D.
      • Haro J.M.
      • Novick D.
      • et al.
      Reasons and outcomes of olanzapine dose adjustments in the outpatient treatment of schizophrenia.
      One of the biggest challenges for long-term treatment is nonadherence with prescribed medication and subsequent relapse.
      • Mortimer A.
      • Williams P.
      • Meddis D.
      Impact of side-effects of atypical antipsychotics on non-compliance, relapse and cost.
      The multiple causes of nonadherence include lack of insight, adverse events, stigma, and/or underestimating the consequences of relapse.
      • Mortimer A.
      • Williams P.
      • Meddis D.
      Impact of side-effects of atypical antipsychotics on non-compliance, relapse and cost.
      • Sajatovic M.
      • Blow F.
      • Kales H.C.
      • et al.
      Age comparison of treatment adherence with antipsychotic medications among individuals with bipolar disorder.
      • Sajatovic M.
      • Biswas K.
      • Kilbourne A.K.
      • et al.
      Factors associated with prospective long-term treatment adherence among individuals with bipolar disorder.
      • Sajatovic M.
      • Ignacio R.V.
      • West J.A.
      • et al.
      Predictors of nonadherence among individuals with bipolar disorder receiving treatment in a community mental health clinic.
      To prevent nonadherence and relapse, clinicians, patients, and payers should work closely as a team. Clinicians may facilitate or implement psychotherapies, psychosocial interventions, and psychoeducation as medication adjuncts that can reduce the risks for nonadherence and relapse.
      • Velligan D.I.
      • Weiden P.J.
      • Sajatovic M.
      • et al.
      Strategies for addressing adherence problems in patients with serious and persistent mental illness: recommendations from the expert consensus guidelines.
      • Devulapalli K.K.
      • Ignacio R.V.
      • Weiden P.
      • et al.
      Why do persons with bipolar disorder stop their medication?.
      Medication-monitoring systems implemented by pharmacies or health care systems may help clinicians and payers to assess adherence behavior
      • Velligan D.I.
      • Weiden P.J.
      • Sajatovic M.
      • et al.
      Strategies for addressing adherence problems in patients with serious and persistent mental illness: recommendations from the expert consensus guidelines.
      and provide a potential opportunity to implement program-, clinic- and individual-level approaches that can enhance adherence. Interventions at the individual level that empower patients to become more actively involved in their own care and may improve both adherence and functional status
      • Sajatovic M.
      • Biswas K.
      • Kilbourne A.K.
      • et al.
      Factors associated with prospective long-term treatment adherence among individuals with bipolar disorder.
      • Devulapalli K.K.
      • Ignacio R.V.
      • Weiden P.
      • et al.
      Why do persons with bipolar disorder stop their medication?.
      are urgently needed.
      To further reduce the risk for nonadherence and relapse, clinicians should communicate potential consequences of relapse to patients and payers. Relapse has an immediate impact on patients' well-being and poses long-term risk for recovery. Data from studies in patients with bipolar disorder and MDD have shown that relapse has a negative effect on cognitive function.
      • Bos E.H.
      • Bouhuys A.L.
      • Geerts E.
      • et al.
      Cognitive, physiological, and personality correlates of recurrence of depression.
      • Elshahawi H.H.
      • Essawi H.
      • Rabie M.A.
      • et al.
      Cognitive functions among euthymic bipolar I patients after a single manic episode versus recurrent episodes.
      Relapse also decreases treatment response in patients with bipolar depression
      • Berk M.
      • Brnabic A.
      • Dodd S.
      • et al.
      Does stage of illness impact treatment response in bipolar disorder? Empirical treatment data and their implication for the staging model and early intervention.
      or MDD.
      • Kaymaz N.
      • van Os J.
      • Loonen A.J.
      • et al.
      Evidence that patients with single versus recurrent depressive episodes are differentially sensitive to treatment discontinuation: a meta-analysis of placebo-controlled randomized trials.
      • Booij L.
      • Van der Does W.
      • Benkelfat C.
      • et al.
      Predictors of mood response to acute tryptophan depletion A reanalysis.
      The discussion of these negative aspects of relapse with patients may decrease the risk for nonadherence and subsequent relapse. This understanding may motivate payers to start new initiatives or strategies to help patients to avoid relapse.

      Communication Based on Disorders

      There are a number of psychotropic drugs with multiple indications in psychiatry. For example, antipsychotics have been approved for the treatment of schizophrenia, bipolar disorder, and MDD. However, the efficacy and tolerability of these drugs vary when the drugs are used for different psychiatric conditions (Table I). In some instances, the use of antipsychotic medication can be perceived as stigmatizing and likely to promote nonadherence among people with psychiatric illness.
      • Sajatovic M.
      • Blow F.
      • Kales H.C.
      • et al.
      Age comparison of treatment adherence with antipsychotic medications among individuals with bipolar disorder.
      An individual with bipolar disorder may avoid taking an antipsychotic medication as he or she perceives it to be a “schizophrenia” drug. Clinicians should thus communicate specific treatment expectations to patients based on that individual's psychiatric disorder to maximize adherence and minimize adverse events.

      Communication Based on Cost

      In the current financial environment, communicating potential benefits and harm of psychiatric treatments and cost to patients and payers has become more important than ever before, but the emphases may be different. At an individual level, the main concern may be about efficacy, adverse events, and cost of treatment, but payers tend to focus on what is most cost-effective. In addition, the priorities and focus among payers may vary greatly.
      • Furiak N.M.
      • Ascher-Svanum H.
      • Klein R.W.
      • et al.
      Cost-effectiveness model comparing olanzapine and other oral atypical antipsychotics in the treatment of schizophrenia in the United States.
      Government-funded health care programs, such as Medicare in the United States, may be interested in the potential short-term benefits and harm of an intervention but equally interested in long-term benefits and harm. Third-party payers, including private insurance companies, may focus on short-term benefits and harm because their policies and coverage renew annually.
      • Furiak N.M.
      • Ascher-Svanum H.
      • Klein R.W.
      • et al.
      Cost-effectiveness model comparing olanzapine and other oral atypical antipsychotics in the treatment of schizophrenia in the United States.

      Generic Versus Branded Drugs

      Prescription drugs account for ∼10% of total health care expenditures in the United States. In 2007, the expenditures for prescription drugs in the United Sates totaled $287 billion. Typically, generic drugs cost 30% to 85% less than their branded counterparts.
      • Lewek P.
      • Kardas P.
      Generic drugs: the benefits and risks of making the switch.
      A typical formulary charges $6 for generic medications, $29 for preferred branded drugs, and $40 or more for nonpreferred branded drugs. Clearly, a small increase in generic drug use will save tens of millions of dollars. For this reason, the federal government, local governments, and third-party payers have encouraged clinicians and patients to use generic drugs.
      Since cost-saving will continue to be a predominant issue in any health care system, patients will often be faced with choosing or switching between generic and branded drugs. However, studies have shown that patients and physicians have negative attitudes toward generic medications,
      • Roman B.
      Patients' attitudes towards generic substitution of oral atypical antipsychotics: a questionnaire-based survey in a hypothetical pharmacy setting.
      • Shrank W.H.
      • Liberman J.N.
      • Fischer M.A.
      • et al.
      Physician perceptions about generic drugs.
      and that the magnitude of comfort with generic substitution and communication with health care providers about their similarities or differences result in more positive perceptions about the use of generic drugs.
      • Roman B.
      Patients' attitudes towards generic substitution of oral atypical antipsychotics: a questionnaire-based survey in a hypothetical pharmacy setting.
      • Shrank W.H.
      • Liberman J.N.
      • Fischer M.A.
      • et al.
      Physician perceptions about generic drugs.
      Without question, clinicians can play an important role in communicating to patients and payers the potential benefits and harm of generic drugs. However, in contrast to the straightforward cost-saving benefits of generic drugs, it is relatively difficult to communicate the potential harm, if any, of generic drugs to patients and payers due to the nature of requirements for generic drugs.
      To be approved by the FDA, the dosage formulation, tolerability, strength, route of administration, quality, performance characteristics, and intended use of a generic drug must be similar to those of a corresponding branded drug. The bioequivalence of a generic drug to its branded counterpart is the key for approval from the FDA or other regulatory agencies. The criteria for bioequivalence have been established using in vitro or in vivo experiments (depending on the drug) according to guidelines set by the FDA.
      • Lewek P.
      • Kardas P.
      Generic drugs: the benefits and risks of making the switch.
      • Berg M.J.
      • Gross R.A.
      • Tomaszewski K.J.
      • et al.
      Generic substitution in the treatment of epilepsy: case evidence of breakthrough seizures.
      The differences and similarities between generic and branded are summarized in Table II.
      Table IIDifferences between generic branded and drugs.
      Overall similarities include ingredients, dosages, strengths, and indications. Overall differences include shape, scoring configuration, release mechanisms, packaging, colors, flavors, preservatives, salts, and expiration date.
      ParameterGenericBranded
      Efficacy/tolerabilityStudies in healthy volunteers (sample size, 18–36 subjects), crossover design, generic vs branded, and single dose to assess bioequivalence and tolerability. Bioequivalence generally defined as the 90% CI of a generic's Cmax and AUC within the range of 80%–125% of that of the branded drug.Vigorous studies in animals and humans, including large, well-powered randomized, double-blind, placebo-controlled studies in patients to show its efficacy. Adverse events are carefully tracked. Bioavailability testing is also required.
      ManufacturersMultiple1
      ApplicationAbbreviated New Drug ApplicationNew Drug Application
      low asterisk Overall similarities include ingredients, dosages, strengths, and indications. Overall differences include shape, scoring configuration, release mechanisms, packaging, colors, flavors, preservatives, salts, and expiration date.
      Although the FDA and other regulatory agencies have established vigorous criteria (bioequivalence to the branded formulation) and a thorough surveillance program for generic drugs, the concern of bioequivalence not being equal to therapeutic equivalence has been raised.
      • Lewek P.
      • Kardas P.
      Generic drugs: the benefits and risks of making the switch.
      • Berg M.J.
      • Gross R.A.
      • Tomaszewski K.J.
      • et al.
      Generic substitution in the treatment of epilepsy: case evidence of breakthrough seizures.
      • Kramer G.
      • Biraben A.
      • Carreno M.
      • et al.
      Current approaches to the use of generic antiepileptic drugs.
      • Desmarais J.E.
      • Beauclair L.
      • Margolese H.C.
      Switching from brand-name to generic psychotropic medications: a literature review.
      • Howland R.H.
      Are generic medications safe and effective?.
      • Margolese H.C.
      • Wolf Y.
      • Desmarais J.E.
      • et al.
      Loss of response after switching from brand name to generic formulations: three cases and a discussion of key clinical considerations when switching.
      • Rosenthal J.
      • Kong B.
      • Jacobs L.
      • et al.
      Did a switch to a generic antidepressant cause relapse?.
      The concern is based on the fact that a generic drug is not required to have efficacy and tolerability identical to its branded counterpart. In fact, there has never been a well-controlled head-to-head comparison study to assess the efficacy and tolerability of a generic drug versus its branded counterpart. Although the FDA had tried to assure the public that generic drugs are equally effective and tolerable, this issue continues to generate debate and confusion.
      • Berg M.J.
      • Gross R.A.
      • Tomaszewski K.J.
      • et al.
      Generic substitution in the treatment of epilepsy: case evidence of breakthrough seizures.
      • Kramer G.
      • Biraben A.
      • Carreno M.
      • et al.
      Current approaches to the use of generic antiepileptic drugs.
      • Desmarais J.E.
      • Beauclair L.
      • Margolese H.C.
      Switching from brand-name to generic psychotropic medications: a literature review.
      • Howland R.H.
      Are generic medications safe and effective?.
      • Margolese H.C.
      • Wolf Y.
      • Desmarais J.E.
      • et al.
      Loss of response after switching from brand name to generic formulations: three cases and a discussion of key clinical considerations when switching.
      • Rosenthal J.
      • Kong B.
      • Jacobs L.
      • et al.
      Did a switch to a generic antidepressant cause relapse?.
      • Kluznik J.C.
      • Walbek N.H.
      • Farnsworth M.G.
      • et al.
      Clinical effects of a randomized switch of patients from clozaril to generic clozapine.
      • van Os S.
      • Relleke M.
      • Piniella P.M.
      Lack of bioequivalence between generic risperidone oral solution and originator risperidone tablets.
      • Chenu F.
      • Batten L.A.
      • Zernig G.
      • et al.
      Comparison of pharmacokinetic profiles of brand-name and generic formulations of citalopram and venlafaxine: a crossover study.
      Data from case reports and small-scale studies have suggested that switching to generic antidepressants,
      • Desmarais J.E.
      • Beauclair L.
      • Margolese H.C.
      Switching from brand-name to generic psychotropic medications: a literature review.
      • Rosenthal J.
      • Kong B.
      • Jacobs L.
      • et al.
      Did a switch to a generic antidepressant cause relapse?.
      antipsychotics,
      • Kluznik J.C.
      • Walbek N.H.
      • Farnsworth M.G.
      • et al.
      Clinical effects of a randomized switch of patients from clozaril to generic clozapine.
      and mood stabilizers
      • Desmarais J.E.
      • Beauclair L.
      • Margolese H.C.
      Switching from brand-name to generic psychotropic medications: a literature review.
      was associated with symptom relapse and/or adverse events. A few pharmacokinetic studies have also shown that some generic drugs were not bioequivalent to their branded counterparts.
      • van Os S.
      • Relleke M.
      • Piniella P.M.
      Lack of bioequivalence between generic risperidone oral solution and originator risperidone tablets.
      • Chenu F.
      • Batten L.A.
      • Zernig G.
      • et al.
      Comparison of pharmacokinetic profiles of brand-name and generic formulations of citalopram and venlafaxine: a crossover study.
      However, after reviewing the existing literature, Howland
      • Howland R.H.
      Are generic medications safe and effective?.
      concluded that there was no consistent evidence that generic drug substitutions were less effective or tolerable.
      The safety concern and controversy on switching from a branded drug to a generic drug have been highlighted by the use of generic antiepileptic drugs (AEDs) in patients with epilepsy.
      • Berg M.J.
      • Gross R.A.
      • Tomaszewski K.J.
      • et al.
      Generic substitution in the treatment of epilepsy: case evidence of breakthrough seizures.
      • Kramer G.
      • Biraben A.
      • Carreno M.
      • et al.
      Current approaches to the use of generic antiepileptic drugs.
      • Kesselheim A.S.
      • Stedman M.R.
      • Bubrick E.J.
      • et al.
      Seizure outcomes following the use of generic versus brand-name antiepileptic drugs: a systematic review and meta-analysis.
      Observational data have suggested that generic substitutions were associated with an increased risk for breakthrough seizures; however, in a recent meta-analysis of seizure outcome following the use of generic versus branded AEDs, Kesslelheim et al
      • Kesselheim A.S.
      • Stedman M.R.
      • Bubrick E.J.
      • et al.
      Seizure outcomes following the use of generic versus brand-name antiepileptic drugs: a systematic review and meta-analysis.
      concluded that data from RCTs did not suggest an association between loss of seizure control and generic drug substitution of at least 3 AEDs. Despite inconsistent evidence, the devastating consequences of potential breakthrough seizures, such as loss of a driver's license, job loss, anxiety, depression, injury, and death when switching from a branded AED to a generic counterpart have led some professional societies and even legislatures worldwide to develop their own guidelines for the use of generic AEDs in patients with epilepsy.
      • Berg M.J.
      • Gross R.A.
      • Tomaszewski K.J.
      • et al.
      Generic substitution in the treatment of epilepsy: case evidence of breakthrough seizures.
      • Kramer G.
      • Biraben A.
      • Carreno M.
      • et al.
      Current approaches to the use of generic antiepileptic drugs.
      • Kesselheim A.S.
      • Stedman M.R.
      • Bubrick E.J.
      • et al.
      Seizure outcomes following the use of generic versus brand-name antiepileptic drugs: a systematic review and meta-analysis.
      Overall recommendations are dependent on individual patient characteristics, such as a history of well-controlled seizure versus uncontrolled seizure, initiation versus continuation phase use, and so on. The majority have emphasized that patients and clinicians should be informed when a branded drug is substituted with a generic counterpart, and the efficacy and tolerability of the generic drug should be monitored closely after the substitution. Since some mood stabilizers for bipolar disorder are anticonvulsants, clinicians should be aware that the comparative efficacy and tolerability of generic anticonvulsants in bipolar disorder are to be determined.
      The findings of reduced efficacy and increased adverse events of generic drugs in case reports and observational studies have been speculated to be due to the “negative placebo” or “nocebo” effect.
      • Howland R.H.
      Are generic medications safe and effective?.
      The nocebo effect might be related to the negative perception of generic drugs so that a patient who switches to a generic drug might be more likely to attribute any adverse event or worsened symptom to the change in medication.
      • Howland R.H.
      Are generic medications safe and effective?.
      If this is the case, communicating to patients with evidence-based findings on generic drugs may minimize the nocebo effect.
      Based on the current FDA requirements for the approval of generic drugs, it is unlikely that large head-to-head comparison studies of generic and branded drugs will be conducted. Therefore, clinicians, patients, and payers will likely continue to deal with this uncertainty. Since there is no consistent evidence suggesting that generic psychotropic drugs are less effective or less tolerable compared with their branded counterparts,
      • Howland R.H.
      Are generic medications safe and effective?.
      • Kesselheim A.S.
      • Stedman M.R.
      • Bubrick E.J.
      • et al.
      Seizure outcomes following the use of generic versus brand-name antiepileptic drugs: a systematic review and meta-analysis.
      the benefit of switching to or initiating treatment with a generic drug for psychiatric disorders is far greater than any potential harm. Clinicians and patients should not hesitate to choose a generic drug if it is indicated and available. To reduce the uneasiness from switching to a generic drug, clinicians should clearly communicate the facts about generic drugs to patients and educate them about the early signs of relapse and newly emerging adverse events on an individual basis. It is also wise to initiate treatment with generics in patients who have never taken a psychiatric medication and in those who have not responded to a current medication to avoid the concern of generic substitution.
      • Kramer G.
      • Biraben A.
      • Carreno M.
      • et al.
      Current approaches to the use of generic antiepileptic drugs.
      • Vlahiotis A.
      • Devine S.T.
      • Eichholz J.
      • et al.
      Discontinuation rates and health care costs in adult patients starting generic versus brand SSRI or SNRI antidepressants in commercial health plans.

      Direct Versus Indirect Costs

      Health care costs include both direct and indirect costs.
      • Polsky D.
      • Doshi J.A.
      • Bauer M.S.
      • et al.
      Clinical trial-based cost-effectiveness analyses of antipsychotic use.
      • McEvoy J.P.
      The costs of schizophrenia.
      The direct costs are fairly straightforward to calculate through pharmacy claims data, hospital reimbursement records, and provider payments. In contrast, calculations of indirect costs are more complicated. However, the majority of studies worldwide have shown that indirect costs exceed direct costs regardless of whether the diagnosis is schizophrenia,
      • McEvoy J.P.
      The costs of schizophrenia.
      MDD,
      • Ivanova J.I.
      • Birnbaum H.G.
      • Kidolezi Y.
      • et al.
      Direct and indirect costs of employees with treatment-resistant and non-treatment-resistant major depressive disorder.
      • Sobocki P.
      • Jonsson B.
      • Angst J.
      • et al.
      Cost of depression in Europe.
      • Wade A.G.
      • Haring J.
      A review of the costs associated with depression and treatment noncompliance: the potential benefits of online support.
      bipolar disorder,
      • Fajutrao L.
      • Locklear J.
      • Priaulx J.
      • et al.
      A systematic review of the evidence of the burden of bipolar disorder in Europe.
      or insomnia.
      • Daley M.
      • Morin C.M.
      • LeBlanc M.
      • et al.
      The economic burden of insomnia: direct and indirect costs for individuals with insomnia syndrome, insomnia symptoms, and good sleepers.
      The cost of caregivers' well-being has also been factored into the indirect-cost profile. In a study of societal costs and quality of life among children with attention deficit hyperactivity disorder (ADHD),
      • Hakkaart-van Roijen L.
      • Zwirs B.W.
      • Bouwmans C.
      • et al.
      Societal costs and quality of life of children suffering from attention deficient hyperactivity disorder (ADHD).
      Roijen et al found that mothers of children with ADHD had increased psychiatric health care costs compared with those whose children did not have behavioral problems. Similarly, family members of patients with bipolar disorder have shown increased use of general and psychiatric health care services.
      • Perlick D.A.
      • Hohenstein J.M.
      • Clarkin J.F.
      • et al.
      Use of mental health and primary care services by caregivers of patients with bipolar disorder: a preliminary study.
      In most cases, payers are more interested in reducing direct costs through various strategies, such as stepped therapy, tiered copayment systems, hospitalization limits, and medication preauthorization. Although these mandatory policies may cut costs,
      • Vlahiotis A.
      • Devine S.T.
      • Eichholz J.
      • et al.
      Discontinuation rates and health care costs in adult patients starting generic versus brand SSRI or SNRI antidepressants in commercial health plans.
      • Chen J.
      • Rizzo J.A.
      Drug prices, out-of-pocket payments, and insurer costs: how do payers vary?.
      payers should not neglect the potential negative consequences that may ensue from such policies. When previously stable psychiatric patients were required to switch treatments because clinically indicated and preferred medications were not covered or approved, a significant increase in adverse-event rates occurred. An increase in adverse events was most notable when clinically preferred antipsychotics could not be obtained.
      • West J.C.
      • Rae D.S.
      • Mojtabai R.
      • et al.
      Clinically unintended medication switches and inability to prescribe preferred medications under Medicare Part D.
      In a related study of the effects of preauthorization among Medicaid beneficiaries with bipolar disorder, Zhang et al
      • Zhang Y.
      • Adams A.S.
      • Ross-Degnan D.
      • et al.
      Effects of prior authorization on medication discontinuation among Medicaid beneficiaries with bipolar disorder.
      found that during the period when preauthorization was required, the use of nonpreferred second-generation antipsychotics and anticonvulsants was reduced. Preauthorization was not associated with increased use of preferred agents, but was associated with an increased rate of treatment discontinuations. Similarly, increased copayments or implementation of a copayment policy can cause patients to decrease or discontinue the medications that they were previously taking.
      • Wagner T.H.
      • Heisler M.
      • Piette J.D.
      Prescription drug co-payments and cost-related medication underuse.
      • Austvoll-Dahlgren A.
      • Aaserud M.
      • Vist G.
      • et al.
      Pharmaceutical policies: effects of cap and co-payment on rational drug use.
      • Hynd A.
      • Roughead E.E.
      • Preen D.B.
      • et al.
      The impact of co-payment increases on dispensings of government-subsidised medicines in Australia.
      Discontinuation of medications due to copayment policies can have unintended consequences, such as nonadherence to treatment, more physician visits, and increased utilization of health care resources.
      • Li X.
      • Guh D.
      • Lacaille D.
      • et al.
      The impact of cost sharing of prescription drug expenditures on health care utilization by the elderly: own- and cross-price elasticities.
      • Anis A.H.
      • Guh D.P.
      • Lacaille D.
      • et al.
      When patients have to pay a share of drug costs: effects on frequency of physician visits, hospital admissions and filling of prescriptions.

      Short-Term Versus Long-Term Costs

      Communication with patients and payers should be focused on potential short-term and long-term benefits, harm, and costs. The short-term considerations of a given intervention are relatively straightforward because the study durations are short, commonly lasting from 3 to 4 weeks for acute mania to 6 to 12 weeks for studies in patients with acute depression or schizophrenia. Maintenance studies typically last from 6 months to 2 years. Except for the CATIE (Clinical Antipsychotic Trial of Intervention Effectiveness) study,
      • Lieberman J.A.
      • Stroup T.S.
      • McEvoy J.P.
      • et al.
      Effectiveness of antipsychotic drugs in patients with chronic schizophrenia.
      no published large-scale studies have compared the efficacy and tolerability of multiple drugs in any psychiatric condition. Despite the innovative nature of the trial, even CATIE has been criticized for having a flawed design.
      • Kraemer H.C.
      • Glick I.D.
      • Klein D.F.
      Clinical trials design lessons from the CATIE study.
      Although that study lasted 18 months, it remains unknown what benefits, harm, and costs would emerge after several years had the patients continued taking their medications. It is well known that long-term treatment with psychotropic drugs can cause side effects such as tardive dyskinesia, weight gain, and metabolic syndrome. These potential effects with long-term treatment may increase the burden on patients and society and increase the costs to payers.
      On the other hand, some interventions may cost more in the beginning, but will save money over the long run. Data have shown that psychosocial interventions in patients with schizophrenia or bipolar disorder cost more in the beginning but cost less over time.
      • Scott J.
      • Colom F.
      • Popova E.
      • et al.
      Long-term mental health resource utilization and cost of care following group psychoeducation or unstructured group support for bipolar disorders: a cost-benefit analysis.
      • Simon G.E.
      • Ludman E.J.
      • Bauer M.S.
      • et al.
      Long-term effectiveness and cost of a systematic care program for bipolar disorder.
      Patients and payers should be informed of the potential short- and long-term benefits, harm, and costs before initiating a treatment or implementing a new policy.

      Communication Based on Effectiveness

      Efficacy Versus Effectiveness

      It is important to convey to patients and payers the differences between efficacy and effectiveness. Although there are no “gold-standard” criteria for an efficacy or effectiveness study,
      • Gartlehner G.
      • Hansen R.A.
      • Nissman D.
      • et al.
      efficacy trials determine whether an intervention produces the expected results under ideal circumstances, and effectiveness trials measure the degree of beneficial effect in clinical practice. Data from effectiveness studies are more generalizable than are those from efficacy studies. To assist clinicians, researchers, and policy makers to understand these 2 kinds of studies, especially for systematic reviews, the Agency for Healthcare Research and Quality of the United States Department of Health and Human Services has proposed that at least 6 of 7 criteria be used to distinguish efficacy studies from effectiveness studies.
      • Gartlehner G.
      • Hansen R.A.
      • Nissman D.
      • et al.
      To date, only a few effectiveness studies have been published: the CATIE study for schizophrenia, the STEP-BD (Systematic Treatment Enhancement Program for Bipolar Disorder), and the STAR*D (Sequenced Treatment Alternatives to Relieve Depression) study for MDD treatments (all funded by the National Institute of Mental Health), and the BALANCE (Bipolar Affective Disorder: Lithium/Anticonvulsant Evaluation) study (supported by the Stanley Foundation).

      Comorbidity and Effectiveness

      Comorbidity in psychiatric disorders is the rule rather than the exception. Epidemiologic and clinical studies have shown that “pure” bipolar disorder, MDD, or anxiety disorders are rare.
      • Kessler R.C.
      • Chiu W.T.
      • Demler O.
      • et al.
      Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication.
      • Merikangas K.R.
      • Ames M.
      • Cui L.
      • et al.
      The impact of comorbidity of mental and physical conditions on role disability in the US adult household population.
      In addition, medical comorbidity is common in psychiatric patients.
      • Kemp D.E.
      • Gao K.
      • Chan P.K.
      • et al.
      Medical comorbidity in bipolar disorder: relationship between illnesses of the endocrine/metabolic system and treatment outcome.
      • Fagiolini A.
      • Goracci A.
      The effects of undertreated chronic medical illnesses in patients with severe mental disorders.
      Patients with comorbidities are commonly excluded from efficacy trials. According to the STAR*D data, only about a quarter of patients with MDD would be eligible for a conventional efficacy trial.
      • Rush A.J.
      Star-D: lessons learned and future implications.
      Similarly, only about 20% of patients with bipolar disorder would be eligible for a typical efficacy clinical trial.
      • Talamo A.
      • Baldessarini R.J.
      • Centorrino F.
      Comparison of mania patients suitable for treatment trials versus clinical treatment.
      In studies of the effectiveness of treatments of bipolar disorder and MDD, comorbid anxiety and/or substance use disorders were associated with decreased responses to treatments or an altered course of illness.
      • Otto M.W.
      • Simon N.M.
      • Wisniewski S.R.
      • et al.
      Prospective 12-month course of bipolar disorder in out-patients with and without comorbid anxiety disorders.
      • Fava M.
      • Rush A.J.
      • Alpert J.E.
      • et al.
      Difference in treatment outcome in outpatients with anxious versus nonanxious depression: a STAR*D report.
      • Howland R.H.
      • Rush A.J.
      • Wisniewski S.R.
      • et al.
      Concurrent anxiety and substance use disorders among outpatients with major depression: clinical features and effect on treatment outcome.
      Similarly, comorbid medical conditions have been associated with poorer treatment outcomes.
      • Kemp D.E.
      • Gao K.
      • Chan P.K.
      • et al.
      Medical comorbidity in bipolar disorder: relationship between illnesses of the endocrine/metabolic system and treatment outcome.
      However, no published large-scale studies have been designed specifically to treat comorbidities such as anxiety disorders, substance use disorders, and ADHD in patients with schizophrenia, bipolar disorder, or MDD. Therefore, clinicians can either “ignore” these comorbidities or treat them “off-label” with medications that have been approved based on efficacy studies in relatively “pure” patient populations. Consequently, polypharmacy has become common.
      • Goldberg J.F.
      • Brooks J.O.
      • Kurita K.
      • et al.
      Depressive illness burden associated with complex polypharmacy in patients with bipolar disorder: findings from the STEP-BD.
      • McIntyre R.S.
      • Jerrell J.M.
      Polypharmacy in children and adolescents treated for major depressive disorder: a claims database study.
      Polypharmacy not only increases the costs to patients and payers but also potentially causes more side effects. For instance, the use of atypical antipsychotic polytherapy in bipolar disorder has been associated with increased adverse events and health care resource utilization but not with improved clinical outcomes.
      • Brooks J.O.
      • Goldberg J.F.
      • Ketter T.A.
      • et al.
      Safety and tolerability associated with second-generation antipsychotic polytherapy in bipolar disorder: findings from the Systematic Treatment Enhancement Program for Bipolar Disorder.
      In contrast, the combination of an antipsychotic + a conventional mood stabilizer is generally more effective than monotherapy with a mood stabilizer for bipolar mania.
      • Smith L.A.
      • Cornelius V.
      • Warnock A.
      • et al.
      Acute bipolar mania: a systematic review and meta-analysis of co-therapy vs. monotherapy.
      Thus, clinical indications for the appropriate use of polytherapy, including the presence of comorbid conditions, must be addressed to more effectively treat acute symptoms, prevent relapse, and improve quality of life. Clearly, it is crucial for clinicians to communicate to patients and payers the limitations of current treatment modalities and the potential consequences of inadequately addressing these comorbidities.

      Communication Based on Cost-Effectiveness

      Information on cost-effectiveness has become increasingly important for clinicians, patients, and payers to choose the most cost-effective treatment for a patient. However, no published studies have been designed with cost-effectiveness as the primary outcome, and such a study is unlikely to be conducted in the near future given the difficulty, time-consuming nature, and cost.
      • Chisholm D.
      Choosing cost-effective interventions in psychiatry: results from the CHOICE programme of the World Health Organization.
      For comparing results of cost-effectiveness study/analysis, 2 measures have been proposed. One is the disability-adjusted life-year (DALY), a time-based measure that combines in a single indicator the years of life lost from premature death and the years of life lived with a disability.
      • Ioannidis J.P.
      • Garber A.M.
      Individualized cost-effectiveness analysis.
      The other is the cost of a medical technology/treatment per quality-adjusted life-year (QALY) achieved, also known as the incremental cost-effectiveness ratio (ICER).
      • Ioannidis J.P.
      • Garber A.M.
      Individualized cost-effectiveness analysis.
      It is a formal economic tool used for comparing the relative value of medical technologies/treatments.
      • Furiak N.M.
      • Ascher-Svanum H.
      • Klein R.W.
      • et al.
      Cost-effectiveness model comparing olanzapine and other oral atypical antipsychotics in the treatment of schizophrenia in the United States.
      • Polsky D.
      • Doshi J.A.
      • Bauer M.S.
      • et al.
      Clinical trial-based cost-effectiveness analyses of antipsychotic use.
      • Ioannidis J.P.
      • Garber A.M.
      Individualized cost-effectiveness analysis.
      QALYs incorporate length of survival and quality of life into a single measure. Values generally range between 0 (death) and 1 (perfect health). A health state with a utility value of 0.8 indicates that a year lived in that state is worth 0.8 year lived in perfect health.
      So far, cost-effectiveness data have been derived in 2 ways, model-based evaluations and trial-based evaluations.
      • Furiak N.M.
      • Ascher-Svanum H.
      • Klein R.W.
      • et al.
      Cost-effectiveness model comparing olanzapine and other oral atypical antipsychotics in the treatment of schizophrenia in the United States.
      • Polsky D.
      • Doshi J.A.
      • Bauer M.S.
      • et al.
      Clinical trial-based cost-effectiveness analyses of antipsychotic use.
      Model-based evaluations use assumptions and simulations to estimate the cost-effectiveness of different interventions for patients with a specific disorder in a certain period.
      • Furiak N.M.
      • Ascher-Svanum H.
      • Klein R.W.
      • et al.
      Cost-effectiveness model comparing olanzapine and other oral atypical antipsychotics in the treatment of schizophrenia in the United States.
      Trial-based evaluations use the data from a specific trial to estimate the cost-effectiveness of studied interventions for a specific disorder.
      • Polsky D.
      • Doshi J.A.
      • Bauer M.S.
      • et al.
      Clinical trial-based cost-effectiveness analyses of antipsychotic use.
      Both types of evaluation have advantages and disadvantages; however, in some instances, 2 types of analyses can generate conflicting results.
      By using a Monte Carlo microsimulation model, Furiak et al
      • Furiak N.M.
      • Ascher-Svanum H.
      • Klein R.W.
      • et al.
      Cost-effectiveness model comparing olanzapine and other oral atypical antipsychotics in the treatment of schizophrenia in the United States.
      analyzed data from the CATIE study and others and found that the use of olanzapine (0.733 QALYs) was associated with better clinical outcomes and lower total direct health care costs compared with generic risperidone (0.719), quetiapine (0.708), ziprasidone (0.715), and aripiprazole (0.710) in the treatment of schizophrenia.
      By using the same CATIE data in a trial-based cost-effectiveness analysis, Rosenheck et al
      • Rosenheck R.A.
      • Leslie D.L.
      • Sindelar J.
      • et al.
      Cost-effectiveness of second-generation antipsychotics and perphenazine in a randomized trial of treatment for chronic schizophrenia.
      found no significant differences in the cost-effectiveness measure of QALY ratings among olanzapine (0.717 QALYs), risperidone (0.704), quetiapine (0.718), and ziprasidone (0.716), although the typical antipsychotic perphenazine (0.720) was associated with higher QALY ratings than other agents.
      Similarly, in a study of using the Markov model to analyze the cost-effectiveness of pharmacologic (typical antipsychotics, generic risperidone, olanzapine, and clozapine) and psychosocial (family interventions) interventions for schizophrenia, Phanthunane et al
      • Phanthunane P.
      • Vos T.
      • Whiteford H.
      • et al.
      Cost-effectiveness of pharmacological and psychosocial interventions for schizophrenia.
      found that generic risperidone plus a family intervention was the most cost-effective choice. Clearly, until an uniform cost-effectiveness study design/analysis is implemented, clinicians, patients, and payers have to face the uncertainty of cost-effectiveness data and conflicting findings.
      Undoubtedly, high-quality cost-effectiveness data can help clinicians and patients to choose the most appropriate treatment and help payers to allocate resources. Unless payers design and carry out their own cost-effectiveness studies or analyses, the bias for a manufacturer's own product cannot be avoided. Therefore, basing decisions purely on the current cost-effectiveness data might have negative effects for patients and payers.

      Conclusions

      Evidence-based communication of potential benefits and harm to patients and payers is essential for high-quality care. Simple and easy-to-understand measures like NNTB and NNTH should be used to communicate the data from efficacy and effectiveness studies. Phase-, duration-, and disease-dependent approaches will maximize benefits and minimize harm. Communicating the potential advantages and disadvantages of switching from branded drugs to generic drugs, of focusing on direct versus indirect costs and short-term versus long-term costs, and limitations of current efficacy and effectiveness studies will all serve to reduce costs without compromising the quality of patient care.

      Acknowledgments

      Dr. Calabrese has received federal funding from the Department of Defense, Health Resources Services Administration and National Institute of Mental Health. Dr. Calabrese has also received research support from Abbott Laboratories Inc., AstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb Co., Cephalon Inc., Cleveland Foundation, Eli Lilly and Co., GlaxoSmithKline, Janssen Pharmaceutica Inc., NARSAD (National Alliance for Research on Schizophrenia and Depression), Repligen Corporation, Stanley Medical Research Institute, Takeda Pharmaceuticals North America Inc., and Wyeth Pharmaceuticals. Dr. Calabrese has received consultant's fees from or been a member of the advisory boards of Abbott, AstraZeneca, Bristol-Myers Squibb, Cephalon, Dainippon Sumitomo Pharma Co. Ltd., EPI-Q Inc., Forest Laboratories Inc., France Foundation, GlaxoSmithKline, Janssen, Johnson & Johnson Services Inc., Lundbeck A/S, Merck & Co Inc., Neurosearch A/S, Ortho-McNeil-Janssen Pharmaceuticals Inc., Otsuka America Pharmaceutical Inc., Pfizer Inc., Repligen, Schering-Plough Corporation (now Merck), Servier, Solvay Pharmaceuticals GmbH, Supernus Pharmaceuticals Inc., Synosia Therapeutics (now Biotie Therapies Corporation), Takeda, and Wyeth. Dr. Calabrese has provided continuing medical education lectures supported by AstraZeneca, Bristol-Myers Squibb, France Foundation, GlaxoSmithKline, Janssen, Johnson & Johnson, Merck, The sanofi-aventis Group, Schering-Plough (now Merck), Pfizer, Solvay, and Wyeth. Dr. Gao has received grant support from AstraZeneca , NARSAD , and the Cleveland Foundation and has received consultant's fees from Merck and Pfizer. Dr. Kemp is a member of the speakers' bureaus of AstraZeneca and Pfizer and has received consultant's fees from Bristol-Myers Squibb. Dr. Sajatovic has received research grants from AstraZeneca , GlaxoSmithKline , Merck , Ortho-McNeil-Janssen , and Pfizer , and has received consultant's fees from Cognition Group and United BioSource Corporation. Dr. Sajatovic has received royalties from Johns Hopkins University Press, Oxford Press, and Springer Press. Dr. Wu expresses her gratitude to the World Psychiatric Association for providing financial support for her fellowship. The authors have indicated that they have no other conflicts of interest with regard to the content of this article.

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