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Original Investigation |

Comparative Mortality Risk in Adult Patients With Schizophrenia, Depression, Bipolar Disorder, Anxiety Disorders, and Attention-Deficit/Hyperactivity Disorder Participating in Psychopharmacology Clinical Trials

Arif Khan, MD1,2; James Faucett, MS1; Shaneta Morrison, AA1; Walter A. Brown, MD3,4
[+] Author Affiliations
1Northwest Clinical Research Center, Bellevue, Washington
2Department of Psychiatry, Duke University School of Medicine, Durham, North Carolina
3Department of Psychiatry and Human Behavior, Brown University, Providence, Rhode Island
4Tufts University School of Medicine, Boston, Massachusetts
JAMA Psychiatry. 2013;70(10):1091-1099. doi:10.1001/jamapsychiatry.2013.149.
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Importance  There is concern that increased mortality risk among patients with psychiatric illness may be worsened by psychopharmacological agents.

Objectives  To assess mortality risk among adult patients with a diagnosis of schizophrenia, depression, bipolar disorder, anxiety disorders, or attention-deficit/hyperactivity disorder participating in clinical trials conducted by pharmaceutical companies for US Food and Drug Administration (FDA) approval to market and to evaluate if psychopharmacological agents worsen this risk.

Data Sources  The FDA Summary Basis of Approval (SBA) reports of new drug applications and supplemental applications for 28 psychopharmacological agents approved between 1990 and 2011.

Study Selection  The FDA SBA reports detailing exposure data from acute placebo-controlled trials and safety extension studies including 92 542 patients from 47 adult drug approval programs for treatment of schizophrenia, depression, bipolar disorder, anxiety disorders, or attention-deficit/hyperactivity disorder and SBA reports on combination and maintenance therapy programs for treatments of bipolar disorder.

Data Extraction and Synthesis  We reviewed and synthesized mortality data from SBA reports that combined mortality rates across the clinical trials, including information on patient exposure years (PEY) for active treatments and placebo for individual indications.

Main Outcomes and Measures  Overall mortality rate per 100 000 PEY in relation to the psychiatric diagnosis of the patients participating in psychopharmacology clinical trials. Also, the overall mortality rates using PEY technique among patients assigned to psychopharmacological agents or placebo were evaluated.

Results  Overall, mortality risk was high and significantly associated with psychiatric diagnosis (χ24 = 1760; P < .001). Compared with the general adult population, patients with schizophrenia had the highest mortality risk (3.8-fold increase), followed by patients with depression (3.15-fold increase) and bipolar disorder (3.0-fold increase). The mortality risk was not increased when patients were assigned to psychotropic agents rather than placebo except for heterocyclic antidepressants. Suicide accounted for 109 of all 265 deaths (41.1%).

Conclusions and Relevance  These data suggest that increased mortality rates reported in population studies are detectable among adult patients with psychiatric illnesses participating in psychopharmacological trials. Furthermore, 3- to 4-month exposure to modern psychotropic agents, such as atypical antipsychotic agents, selective serotonin reuptake inhibitors, and selective serotonin-norepinephrine reuptake inhibitors does not worsen this risk. Given the inherent limitations of the FDA SBA reports, further research is needed to support firm conclusions.

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Figures

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Figure 1.
Total Mortality and Suicide Rates per 100 000 Patient Exposure Years (PEY) From Clinical Trials Conducted During New Drug Approval Programs in Adults

Total mortality and suicide risk (per 100 000 PEY) during acute and safety extension phases of clinical trials conducted to approve drugs for treatment of psychiatric disorders in adults. Data were obtained from US Food and Drug Administration Summary Basis of Approval reports with available PEY and corresponding mortality totals (see the Methods section for details). Anxiety disorder spectrum is inclusive of patients diagnosed with obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, generalized anxiety disorder, and social anxiety disorder. Error bars represent 95% confidence intervals for mortality and suicide rates (we could not estimate these for suicide rates in patients with anxiety owing to the limited number of observations). No deaths occurred among patients enrolled in adult clinical trials for attention-deficit/hyperactivity disorder (ADHD). Overall mortality rates differed significantly between patients on the basis of diagnosis (schizophrenia, bipolar disorder, depression, anxiety disorder, or ADHD) (χ24 = 1760; P < .001). Post hoc analysis with Bonferroni correction for multiple comparisons revealed a significant difference in overall mortality rates between patients with schizophrenia, bipolar disorder, or depression (χ22 = 32.4; P < .001).

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Figure 2.
Relationship Between Psychotropic Agents and Overall Mortality Risk Compared With Overall Mortality Risk With Placebo

Odds ratios were calculated by using mortality rates (per 100 000 patient exposure years) for patients assigned to active treatment or control arms based on mortality and exposure data from Food and Drug Administration Summary Basis of Approval reports. Mortality rates are not included for attention-deficit/hyperactivity disorder (ADHD) because no deaths occurred during the ADHD clinical trials. Atypical antipsychotic agents for schizophrenia included olanzapine, ziprasidone, risperidone, quetiapine, aripiprazole, asenapine, quetiapine sustained release, paliperidone, and iloperidone. Agents approved for bipolar disorder included atypical antipsychotic agents olanzapine, ziprasidone, risperidone, quetiapine, aripiprazole, and asenapine; mood stabilizers lithium carbonate, divalproex sodium, and carbamazepine; and combinations of atypical antipsychotic agents and mood stabilizers. Serotonergic antidepressants included selective serotonin reuptake inhibitors (SSRIs) (sertraline, paroxetine, paroxetine controlled release (CR), citalopram, and escitalopram), selective serotonin-norepinephrine reuptake inhibitors (SNRIs; venlafaxine, venlafaxine extended release (XR), duloxetine, and desvenlafaxine), and SSRIs plus nefazodone, trazodone, or vilazodone. Heterocyclic antidepressant agents included imipramine, amitryptiline, maprotiline, and mirtazapine. Anti-anxiety agents included fluoxetine, paroxetine, clonazepam, venlafaxine XR, and paroxetine CR.

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Figure 3.
Relationship Between Psychotropic Agents and Suicide Risk Compared With Suicide Risk With Placebo

Odds ratios were calculated by using suicide rates (per 100 000 patient exposure years) for patients assigned to active treatment or control arms based on suicide and exposure data from Food and Drug Administration Summary Basis of Approval reports. Suicide rates are not included for attention-deficit/hyperactivity disorder (ADHD) because no suicides occurred during the ADHD clinical trials. A suicide comparison is not included for bipolar disorders because no suicides occurred in placebo arms of bipolar disorder clinical trials (see Table 5 for details). Atypical antipsychotic agents for treatment of schizophrenia include olanzapine, ziprasidone, risperidone, quetiapine, aripiprazole, asenapine, quetiapine sustained release, paliperidone, and iloperidone. Serotonergic antidepressants included selective serotonin reuptake inhibitors (SSRIs) (sertraline, paroxetine, paroxetine CR (controlled release), citalopram, and escitalopram), selective serotonin-norepinephrine reuptake inhibitors (SNRIs; venlafaxine, venlafaxine extended release (XR), duloxetine, and desvenlafaxine, and SSRIs plus nefazodone, trazodone, or vilazodone. Heterocyclic antidepressant agents included imipramine, amitryptiline, maprotiline, and mirtazapine. Anti-anxiety agents included fluoxetine, paroxetine, clonazepam, venlafaxine XR, and paroxetine CR.

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