Optimizing the clinical utility of four proposed criteria for a persistent and impairing grief disorder by emphasizing core, rather than associated symptoms.

BACKGROUND: Distinguishing a disorder of persistent and impairing grief from normative grief allows clinicians to identify this often undetected and disabling condition. As four diagnostic criteria sets for a grief disorder have been proposed, their similarities and differences need to be elucidated. METHODS: Participants were family members bereaved by US military service death (N = 1732). We conducted analyses to assess the accuracy of each criteria set in identifying threshold cases (participants who endorsed baseline Inventory of Complicated Grief ⩾30 and Work and Social Adjustment Scale ⩾20) and excluding those below this threshold. We also calculated agreement among criteria sets by varying numbers of required associated symptoms. RESULTS: All four criteria sets accurately excluded participants below our identified clinical threshold (i.e. correctly excluding 86-96% of those subthreshold), but they varied in identification of threshold cases (i.e. correctly identifying 47-82%). When the number of associated symptoms was held constant, criteria sets performed similarly. Accurate case identification was optimized when one or two associated symptoms were required. When employing optimized symptom numbers, pairwise agreements among criteria became correspondingly 'very good' (κ = 0.86-0.96). CONCLUSIONS: The four proposed criteria sets describe a similar condition of persistent and impairing grief, but differ primarily in criteria restrictiveness. Diagnostic guidance for prolonged grief disorder in International Classification of Diseases, 11th Edition (ICD-11) functions well, whereas the criteria put forth in Section III of Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) are unnecessarily restrictive.

Complicated grief therapy for clinicians: An evidence-based protocol for mental health practice.

In the United States alone, about 10 million persons are newly bereaved each year. Most do not require professional intervention or treatment, but many can benefit from targeted support. However, a significant minority of bereaved persons experience intense, prolonged and disabling grief symptoms associated with considerable morbidity and mortality (aka, "Complicated Grief"). Individuals with Complicated Grief require more formal interventions. In this article, we describe a compassionate and evidence-based approach to bereavement-care that can be provided in varied mental health settings. For individuals struggling with acute grief, clinicians can help by providing recognition and acceptance of the grief, eliciting and compassionately listening to their narratives of their relationship with the deceased and the death, and regularly "checking in" regarding their grief experiences. For bereaved persons who are experiencing Complicated Grief, we recommend an evidence-based approach to bereavement-care, complicated grief therapy (CGT), that involves helping the individual accept and cope with the loss while simultaneously assisting them with adaptation to life without the deceased. We describe ways of implementing CGT's seven core themes: (1) understanding and accepting grief, (2) managing painful emotions, (3) planning for a meaningful future, (4) strengthening ongoing relationships, (5) telling the story of the death, (6) learning to live with reminders, and (7) establishing an enduring connection with memories of the person who died. This work can be done in a variety of settings, taking into consideration the needs of the patient, the limitations of the setting, and the skills and experiences of each clinician.

Changes in typical beliefs in response to complicated grief treatment.

BACKGROUND: Prolonged grief disorder (PGD) is a new diagnosis in the 11th edition of the International Classification of Diseases, estimated to affect 1 in 10 bereaved people and causing significant distress and impairment. Maladaptive thoughts play an important role in PGD. We have previously validated the typical beliefs questionnaire (TBQ), which contains five kinds of thinking commonly seen in PGD: protesting the death, negative thoughts about the world, needing the person, less grief is wrong, and grieving too much. The current paper examines the role of maladaptive cognition as measured by the TBQ in PGD and its change with treatment. METHODS: Among participants in a multisite clinical trial including 394 adults, we examined (a) the relationship between maladaptive thoughts at baseline and treatment outcomes, (b) the relationship between maladaptive thoughts and suicidality at baseline and posttreatment, and (c) the effect of treatment with and without complicated grief therapy (CGT) on maladaptive thinking. RESULTS: TBQ scores were associated with treatment outcomes and were strongly related to suicidal thinking before and after treatment. TBQ scores showed significantly greater reduction in participants who received CGT with citalopram versus citalopram alone (adjusted mean standard error [SE] difference, -2.45 [0.85]; p = .004) and those who received CGT with placebo versus placebo alone (adjusted mean [SE] difference, -3.44 [0.90]; p < .001). CONCLUSIONS: Maladaptive thoughts, as measured by the TBQ, have clinical and research significance for PGD and its treatment.

Commentary on evidence in support of a grief-related condition as a DSM diagnosis.

The death of a loved one is one of life's greatest stressors. Most bereaved individuals experience a period of acute grief that diminishes in intensity as they adapt to the changes brought about by their loss. Over the past four decades, a growing body of research has focused on a form of prolonged grief that is painful and impairing. There is a substantial and growing evidence base that supports the validity and significance of a grief-related disorder, including the clinical value of being able to diagnose it and provide effective targeted treatment. ICD-11 will include a new diagnosis of prolonged grief disorder (PGD). DSM-5 called this condition persistent complex bereavement disorder (PCBD) and included it in Section III, signaling agreement that a diagnosis is warranted while further research is needed to determine the optimal criteria. Given the remaining uncertainties, reading this literature can be confusing. There is inconsistency in naming the condition (including complicated grief as well as PGD and PCBD) and lack of uniformity in identifying it, with respect to the optimal threshold and timeframe for distinguishing it from normal grief. As an introductory commentary for this Depression and Anxiety special edition on this form of grief, the authors discuss the history, commonalities, and key areas of variability in identifying this condition. We review the state of diagnostic criteria for DSM-5 and the current ICD-11 diagnostic guideline, highlighting the clinical relevance of making this diagnosis.

Prolonged grief disorder: clinical utility of ICD-11 diagnostic guidelines.

BACKGROUND: The World Health Organization (WHO) International Classification of Disease (ICD-11) is expected to include a new diagnosis for prolonged grief disorder (ICD-11PGD). This study examines the validity and clinical utility of the ICD-11PGD guideline by testing its performance in a well-characterized clinical sample and contrasting it with a very different criteria set with the same name (PGDPLOS). METHODS: We examined data from 261 treatment-seeking participants in the National Institute of Mental Health (NIMH)-sponsored multicenter clinical trial to determine the rates of diagnosis using the ICD-11PGD guideline and compared these with diagnosis using PGDPLOS criteria. RESULTS: The ICD-11PGD guideline identified 95.8% [95% confidence interval (CI) 93.3-98.2%] of a treatment-responsive cohort of patients with distressing and impairing grief. PGDPLOS criteria identified only 59.0% (95% CI 53.0-65.0%) and were more likely to omit those who lost someone other than a spouse, were currently married, bereaved by violent means, or not diagnosed with co-occurring depression. Those not diagnosed by PGDPLOS criteria showed the same rate of treatment response as those who were diagnosed. CONCLUSIONS: The ICD-11PGD diagnostic guideline showed good performance characteristics in this sample, while PGDPLOS criteria did not. Limitations of the research sample used to derive PGDPLOS criteria may partly explain their poor performance in a more diverse clinical sample. Clinicians and researchers need to be aware of the important difference between these two identically named diagnostic methods.

Lack of Early Improvement with Antipsychotics is a Marker for Subsequent Nonresponse in Behavioral and Psychological Symptoms of Dementia: Analysis of CATIE-AD Data.

OBJECTIVE: Prediction of response or nonresponse to antipsychotics is especially important in patients with behavioral and psychological symptoms of dementia (BPSD) in whom antipsychotic exposure increases risks of death. This study examined whether the presence or absence of early improvement of BPSD with antipsychotics is associated with subsequent response or nonresponse. METHODS: In a post-hoc analysis of the Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer's Disease (CATIE-AD) study (2001-2004) (clinicaltrials.gov; NCT00015548) in 45 U.S. sites, 245 subjects (olanzapine, N = 90; quetiapine, N = 81; risperidone, N = 74) with a DSM-IV diagnosis of dementia of the Alzheimer type who presented with a score of 1 or more in the Brief Psychiatric Rating Scale (BPRS) at baseline (phase I of CATIE-AD) were randomly assigned to treatment with olanzapine, quetiapine, risperidone, or placebo in a double-blind manner. Associations were examined between response at week 8 and demographic and clinical characteristics, including BPRS total score reduction at week 2, using logistic regression analyses. Prediction performance of binary classification (presence or absence) of improvement or no improvement at week 2 for response at week 8 was examined. RESULTS: BPRS total score reduction at week 2 (mean percentage score reduction: 12.6%) was significantly associated with response at week 8 (odds ratio: 1.18; 95% CI: 1.11-1.26). The 5% score reduction cut-off at week 2 showed the highest accuracy (0.71), with sensitivity, specificity, and positive and negative predictivevalues of 0.76, 0.65, 0.69, and 0.72, respectively. CONCLUSION: Lack of even a very small early improvement with antipsychotic treatment may be a marker of subsequent nonresponse in BPSD.

Measuring Maladaptive Cognitions in Complicated Grief: Introducing the Typical Beliefs Questionnaire.

OBJECTIVES: Maladaptive cognitions related to loss are thought to contribute to development of complicated grief and are crucial to address in treatment, but tools available to assess them are limited. This paper introduces the Typical Beliefs Questionnaire (TBQ), a 25-item self-report instrument to assess cognitions that interfere with adaptation to loss. DESIGN: Study participants completed an assessment battery during their initial evaluation and again after completing treatment at 20 weeks. Test-retest reliability was assessed on a subsample of the participants who did not show change in complicated grief severity after the first 4 weeks of treatment. To examine latent structure of the TBQ, an exploratory factor analysis (EFA) was performed. SETTING: Academic medical centers in Boston, New York, Pittsburgh, and San Diego from 2010-2014. PARTICIPANTS: 394 bereaved adults who met criteria for complicated grief. MEASUREMENTS: The TBQ along with assessments of complicated grief symptoms and related avoidance, depression symptoms, functional impairment, and perceived social support. RESULTS: The TBQ exhibited good internal consistency (α = 0.82) and test-retest reliability (N = 105; intraclass correlation coefficient = 0.74). EFA indicated a five-factor structure: "Protesting the Death," "Negative Thoughts About the World," "Needing the Person," "Less Grief is Wrong" and "Grieving Too Much." The total score and all factors showed sensitivity to change with treatment. CONCLUSIONS: This new tool allows a clinician to quickly and reliably ascertain presence of specific maladaptive cognitions related to complicated grief, and subsequently, to use the information to aid a diagnostic assessment, to structure the treatment, and to measure treatment outcomes.

Complicated grief after suicide bereavement and other causes of death.

The authors compared baseline demographic characteristics, clinical features, and grief-related thoughts, feelings, and behaviors of individuals bereaved by suicide, accident/homicide and natural causes participating in a complicated grief (CG) treatment clinical trial. Severity of CG and depression and current depression diagnosis did not vary by loss type. After adjusting for baseline demographic features, time since death and relationship to the deceased, those with CG after suicide had the highest rates of lifetime depression, preloss passive suicidal ideation, self-blaming thoughts, and impaired work and social adjustment. Even among this treatment-seeking sample of research participants with CG, suicide survivors may face unique challenges.

Bereavement: course, consequences, and care.

This paper discusses each of several potential consequences of bereavement. First, we describe ordinary grief, followed by a discussion of grief gone awry, or complicated grief (CG). Then, we cover other potential adverse outcomes of bereavement, each of which may contribute to, but are not identical with, CG: general medical comorbidity, mood disorders, post-traumatic stress disorder, anxiety, and substance use.

The bereavement exclusion and DSM-5.

BACKGROUND: Pre-DSM-III (where DSM is Diagnostic and Statistical Manual), a series of studies demonstrated that major depressive syndromes were common after bereavement and that these syndromes often were transient, not requiring treatment. Largely on the basis of these studies, a decision was made to exclude the diagnosis of a major depressive episode (MDE) if symptoms could be "better accounted for by bereavement than by MDE" unless symptoms were severe and very impairing. Thus, since the publication of DSM-III in 1980, the official position of American Psychiatry has been that recent bereavement may be an exclusion criterion for the diagnosis of an MDE. This review article attempts to answer the question, "Does the best available research favor continuing the 'bereavement exclusion' (BE) in DSM-5?" We have previously discussed the proposal by the DSM-5 Mood Disorders Work Group to remove the BE from DSM-5. METHODS: Prior reviews have evaluated the validity of the BE based on studies published through 2006. The current review adds research studies published since 2006 and critically examines arguments for and against retaining the BE in DSM-5. RESULTS: The preponderance of data suggests that bereavement-related depression is not different from MDE that presents in any other context; it is equally genetically influenced, most likely to occur in individuals with past personal and family histories of MDE, has similar personality characteristics and patterns of comorbidity, is as likely to be chronic and/or recurrent, and responds to antidepressant medications. CONCLUSIONS: We conclude that the BE should not be retained in DSM-5.

Complicated grief and related bereavement issues for DSM-5.

Bereavement is a severe stressor that typically incites painful and debilitating symptoms of acute grief that commonly progresses to restoration of a satisfactory, if changed, life. Normally, grief does not need clinical intervention. However, sometimes acute grief can gain a foothold and become a chronic debilitating condition called complicated grief. Moreover, the stress caused by bereavement, like other stressors, can increase the likelihood of onset or worsening of other physical or mental disorders. Hence, some bereaved people need to be diagnosed and treated. A clinician evaluating a bereaved person is at risk for both over-and under-diagnosis, either pathologizing a normal condition or neglecting to treat an impairing disorder. The authors of DSM IV focused primarily on the problem of over-diagnosis, and omitted complicated grief because of insufficient evidence. We revisit bereavement considerations in light of new research findings. This article focuses primarily on a discussion of possible inclusion of a new diagnosis and dimensional assessment of complicated grief. We also discuss modifications in the bereavement V code and refinement of bereavement exclusions in major depression and other disorders.

Posttraumatic Distress Symptoms and Their Response to Treatment in Adults With Prolonged Grief Disorder.

OBJECTIVE: Posttraumatic stress disorder and prolonged grief disorder (PGD) arise following major life stressors and may share some overlapping symptomatology. This study aimed to examine the presence and response to treatment of posttraumatic stress symptoms (PTSS) in bereaved adults with a primary diagnosis of PGD. METHODS: A randomized controlled trial of 395 adults with PGD (defined as an Inventory of Complicated Grief score ≥ 30 plus confirmation on structured clinical interview) randomly assigned participants to either complicated grief treatment (CGT) with citalopram, CGT plus placebo, citalopram, or placebo between March 2010 and September 2014. This secondary analysis examined the presence of PTSS (per the Davidson Trauma Scale) at baseline and change in PTSS with treatment using longitudinal mixed-effects regression and examined the role of violent compared to nonviolent deaths (loss type). RESULTS: High levels of PTSS were present at baseline, regardless of loss type, and were associated with increased functional impairment (P < .001). CGT with placebo demonstrated efficacy for PTSS compared to placebo in both threshold (OR = 2.71; 95% CI, 1.13-6.52; P = .026) and continuous (P < .001; effect size d = 0.47) analyses, and analyses were suggestive of a greater effect for CGT plus citalopram compared to citalopram alone (threshold analysis: OR = 2.84; 95% CI, 1.20-6.70; P = .017; continuous analysis: P = .053; d = 0.25). In contrast, citalopram did not differ from placebo, and CGT plus citalopram did not differ from CGT plus placebo. CONCLUSIONS: Bereavement-related PTSS are common in bereaved adults with PGD in the context of both violent and nonviolent death and are associated with poorer functioning. CGT shows efficacy for PTSS, while the antidepressant citalopram does not. TRIAL REGISTRATION: : ClinicalTrials.gov identifier: NCT01179568.

Biomarkers to predict antidepressant response.

During the past several years, we have achieved a deeper understanding of the etiology/pathophysiology of major depressive disorder (MDD). However, this improved understanding has not translated to improved treatment outcome. Treatment often results in symptomatic improvement, but not full recovery. Clinical approaches are largely trial-and-error, and when the first treatment does not result in recovery for the patient, there is little proven scientific basis for choosing the next. One approach to enhancing treatment outcomes in MDD has been the use of standardized sequential treatment algorithms and measurement-based care. Such treatment algorithms stand in contrast to the personalized medicine approach, in which biomarkers would guide decision making. Incorporation of biomarker measurements into treatment algorithms could speed recovery from MDD by shortening or eliminating lengthy and ineffective trials. Recent research results suggest several classes of physiologic biomarkers may be useful for predicting response. These include brain structural or functional findings, as well as genomic, proteomic, and metabolomic measures. Recent data indicate that such measures, at baseline or early in the course of treatment, may constitute useful predictors of treatment outcome. Once such biomarkers are validated, they could form the basis of new paradigms for antidepressant treatment selection.

Mobile interventions for severe mental illness: design and preliminary data from three approaches.

Mobile devices can be used to deliver psychosocial interventions, yet there is little prior application in severe mental illness. We provide the rationale, design, and preliminary data from 3 ongoing clinical trials of mobile interventions developed for bipolar disorder or schizophrenia. Project 1 used a personal digital assistant to prompt engagement in personalized self-management behaviors based on real-time data. Project 2 employed experience sampling through text messages to facilitate case management. Project 3 was built on group functional skills training for schizophrenia by incorporating between-session mobile phone contacts with therapists. Preliminary findings were of minimal participant attrition, and no broken devices; yet, several operational and technical barriers needed to be addressed. Adherence was similar to that reported in nonpsychiatric populations, with high participant satisfaction. Therefore, mobile devices seem feasible and acceptable in augmenting psychosocial interventions for severe mental illness, with future research in establishing efficacy, cost effectiveness, and ethical and safety protocols.

Effectiveness of atypical antipsychotic drugs in patients with Alzheimer's disease.

BACKGROUND: Second-generation (atypical) antipsychotic drugs are widely used to treat psychosis, aggression, and agitation in patients with Alzheimer's disease, but their benefits are uncertain and concerns about safety have emerged. We assessed the effectiveness of atypical antipsychotic drugs in outpatients with Alzheimer's disease. METHODS: In this 42-site, double-blind, placebo-controlled trial, 421 outpatients with Alzheimer's disease and psychosis, aggression, or agitation were randomly assigned to receive olanzapine (mean dose, 5.5 mg per day), quetiapine (mean dose, 56.5 mg per day), risperidone (mean dose, 1.0 mg per day), or placebo. Doses were adjusted as needed, and patients were followed for up to 36 weeks. The main outcomes were the time from initial treatment to the discontinuation of treatment for any reason and the number of patients with at least minimal improvement on the Clinical Global Impression of Change (CGIC) scale at 12 weeks. RESULTS: There were no significant differences among treatments with regard to the time to the discontinuation of treatment for any reason: olanzapine (median, 8.1 weeks), quetiapine (median, 5.3 weeks), risperidone (median, 7.4 weeks), and placebo (median, 8.0 weeks) (P=0.52). The median time to the discontinuation of treatment due to a lack of efficacy favored olanzapine (22.1 weeks) and risperidone (26.7 weeks) as compared with quetiapine (9.1 weeks) and placebo (9.0 weeks) (P=0.002). The time to the discontinuation of treatment due to adverse events or intolerability favored placebo. Overall, 24% of patients who received olanzapine, 16% of patients who received quetiapine, 18% of patients who received risperidone, and 5% of patients who received placebo discontinued their assigned treatment owing to intolerability (P=0.009). No significant differences were noted among the groups with regard to improvement on the CGIC scale. Improvement was observed in 32% of patients assigned to olanzapine, 26% of patients assigned to quetiapine, 29% of patients assigned to risperidone, and 21% of patients assigned to placebo (P=0.22). CONCLUSIONS: Adverse effects offset advantages in the efficacy of atypical antipsychotic drugs for the treatment of psychosis, aggression, or agitation in patients with Alzheimer's disease. (ClinicalTrials.gov number, NCT00015548 [ClinicalTrials.gov].).

Medication augmentation after the failure of SSRIs for depression.

BACKGROUND: Although clinicians frequently add a second medication to an initial, ineffective antidepressant drug, no randomized controlled trial has compared the efficacy of this approach. METHODS: We randomly assigned 565 adult outpatients who had nonpsychotic major depressive disorder without remission despite a mean of 11.9 weeks of citalopram therapy (mean final dose, 55 mg per day) to receive sustained-release bupropion (at a dose of up to 400 mg per day) as augmentation and 286 to receive buspirone (at a dose of up to 60 mg per day) as augmentation. The primary outcome of remission of symptoms was defined as a score of 7 or less on the 17-item Hamilton Rating Scale for Depression (HRSD-17) at the end of this study; scores were obtained over the telephone by raters blinded to treatment assignment. The 16-item Quick Inventory of Depressive Symptomatology--Self-Report (QIDS-SR-16) was used to determine the secondary outcomes of remission (defined as a score of less than 6 at the end of this study) and response (a reduction in baseline scores of 50 percent or more). RESULTS: The sustained-release bupropion group and the buspirone group had similar rates of HRSD-17 remission (29.7 percent and 30.1 percent, respectively), QIDS-SR-16 remission (39.0 percent and 32.9 percent), and QIDS-SR-16 response (31.8 percent and 26.9 percent). Sustained-release bupropion, however, was associated with a greater reduction (from baseline to the end of this study) in QIDS-SR-16 scores than was buspirone (25.3 percent vs. 17.1 percent, P<0.04), a lower QIDS-SR-16 score at the end of this study (8.0 vs. 9.1, P<0.02), and a lower dropout rate due to intolerance (12.5 percent vs. 20.6 percent, P<0.009). CONCLUSIONS: Augmentation of citalopram with either sustained-release bupropion or buspirone appears to be useful in actual clinical settings. Augmentation with sustained-release bupropion does have certain advantages, including a greater reduction in the number and severity of symptoms and fewer side effects and adverse events. (ClinicalTrials.gov number, NCT00021528.).

A call for training the trainers: focus on mentoring to enhance diversity in mental health research.

There is a widening disparity between the proportion of ethnic minority Americans in the population and the number of researchers from these minority groups. One major obstacle in this arena relates to a dearth of mentors for such trainees. The present academic settings are not optimal for development and sustenance of research mentors, especially for mentees from underrepresented minority ethnic groups. Mentoring skills can and should be evaluated and enhanced. Universities, medical schools, and funding agencies need to join hands and implement national- and local-level programs to help develop and reward mentors of junior scientists from ethnic minority groups.

Performance-based and subjective measures of functioning in middle-aged and older adults with bipolar disorder.

Performance-based measures may be useful in quantifying functional impairment associated with bipolar disorder, particularly among older adults. Among 30 outpatients with bipolar disorder and 31 normal comparison subjects (NCs), we administered the UCSD Performance-Based Skills Assessment (UPSA) and 2 subjective measures of functioning. The UPSA simulates real-world everyday tasks, such as financial management. We compared UPSA scores between groups and, within the bipolar group, examined associations between UPSA scores and subjective functioning, cognitive functioning, and depressive, and manic symptoms. By large effect sizes, the bipolar disorder group had lower scores on the UPSA and its subscales compared with NCs. Within the bipolar group, UPSA scores correlated strongly with Quality of Well-Being Scale but not SF-36 scores, and the UPSA was not related to depressive or manic symptoms, but was associated with cognitive functioning. Given its relative independence from symptoms, the UPSA may be useful in gauging the effectiveness of rehabilitation for bipolar disorder.

Disability and self-management practices of people with bipolar disorder: a web-based survey.

In a web-based survey asking adults diagnosed with bipolar disorder about illness management, we obtain frequency of self-reported usage and perceived helpfulness of 27 self-management strategies. We correlated the strategy use and perceived helpfulness with demographic and clinical characteristics, along with the Illness Intrusiveness Scale total score. Completed surveys were obtained from 1,024 individuals. Perceived helpfulness of 18 of 27 strategies was correlated negatively with illness intrusiveness at the P < 0.001 level. Given limitations of web-based surveys, our study underscores the substantial negative impact of bipolar disorder, along with the potential of the Internet to enhance the use of self-management strategies.

Effectiveness of antipsychotic drugs in patients with chronic schizophrenia.

BACKGROUND: The relative effectiveness of second-generation (atypical) antipsychotic drugs as compared with that of older agents has been incompletely addressed, though newer agents are currently used far more commonly. We compared a first-generation antipsychotic, perphenazine, with several newer drugs in a double-blind study. METHODS: A total of 1493 patients with schizophrenia were recruited at 57 U.S. sites and randomly assigned to receive olanzapine (7.5 to 30 mg per day), perphenazine (8 to 32 mg per day), quetiapine (200 to 800 mg per day), or risperidone (1.5 to 6.0 mg per day) for up to 18 months. Ziprasidone (40 to 160 mg per day) was included after its approval by the Food and Drug Administration. The primary aim was to delineate differences in the overall effectiveness of these five treatments. RESULTS: Overall, 74 percent of patients discontinued the study medication before 18 months (1061 of the 1432 patients who received at least one dose): 64 percent of those assigned to olanzapine, 75 percent of those assigned to perphenazine, 82 percent of those assigned to quetiapine, 74 percent of those assigned to risperidone, and 79 percent of those assigned to ziprasidone. The time to the discontinuation of treatment for any cause was significantly longer in the olanzapine group than in the quetiapine (P<0.001) or risperidone (P=0.002) group, but not in the perphenazine (P=0.021) or ziprasidone (P=0.028) group. The times to discontinuation because of intolerable side effects were similar among the groups, but the rates differed (P=0.04); olanzapine was associated with more discontinuation for weight gain or metabolic effects, and perphenazine was associated with more discontinuation for extrapyramidal effects. CONCLUSIONS: The majority of patients in each group discontinued their assigned treatment owing to inefficacy or intolerable side effects or for other reasons. Olanzapine was the most effective in terms of the rates of discontinuation, and the efficacy of the conventional antipsychotic agent perphenazine appeared similar to that of quetiapine, risperidone, and ziprasidone. Olanzapine was associated with greater weight gain and increases in measures of glucose and lipid metabolism.