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GME Research Review

GME Research Review is a monthly newsletter where internationally recognized experts select, summarize, and provide a clinical commentary on the latest published research in psychiatry. Each summary has been derived from the relevant article’s abstract and the clinical commentary has been provided by our expert.


ISSUE 20, November 2013 — Guest Commentator: Michael J. Ostacher, MD, MPH, MMSc, Stanford University School of Medicine, Stanford, CA



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

Khan A, Faucett J, Morrison S, et al
Am J Psychiatry. 2013;70(10):1091-1099.


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 mortality risk.


  • FDA Summary Basis of Approval (SBA) reports for agents approved to treat schizophrenia, ADHD, bipolar disorder, depression, and anxiety disorders including panic disorder, SAD, GAD, OCD, and PTSD between 1990 and 2011 were examined.
  • The mortality data were obtained from the safety sections of the SBA reports, by the diagnosis, by the specific approved indication, by the individual drug, and by cause of death.
  • For schizophrenia, depression, anxiety disorders, and ADHD, all included trials were monotherapy trials for acute treatment of the disorder or safety extension studies of monotherapy treatment.
  • Established the total mortality rates per 100,000 PEY inclusive of patients assigned to investigative agents, comparators, and placebo.
  • Conducted a χ2 analysis to evaluate differences in mortality rates based on indication.

: Overall, mortality risk was high and significantly associated with psychiatric diagnosis (χ24=1,760; P<.001). Compared with the general adult population, patients with schizophrenia had the highest mortality risk, followed by patients with depression and bipolar disorder (Table). 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%).

Psychiatric Diagnosis

Mortality Risk Compared to General Adult Population





Bipolar disorder


Conclusions: These data suggest that increased mortality rates reported in population studies are detectable among adult patients with psychiatric illnesses participating in psychopharmacological trials. Furthermore, 3–4-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.

Clinical Commentary
This study confirms that even amongst the population who agree to participate in FDA registration trials for psychiatric disorders, a presumably healthier population than those ineligible for trials, mortality is increased. While the 3–4-month mortality is not increased for those receiving drug versus placebo, this study does not cover a long enough period to be confident that certain psychiatric drugs (especially those with known metabolic effects such as atypical antipsychotics) do not increase mortality.



Identification of Risk Loci with Shared Effects on Five Major Psychiatric Disorders: A Genome-Wide Analysis

Cross-Disorder Group of the Psychiatric Genomics Consortium
Smoller JW, Craddock N, Kendler K, et al
Lancet. 2013;381(9875):1371-1379.


Objectives: To identify specific variants underlying genetic effects shared between the five disorders in the Psychiatric Genomics Consortium (PCG): autism spectrum disorder, attention-deficit/hyperactivity disorder, bipolar disorder, major depressive disorder, and schizophrenia.


  • The sample for these analyses consisted of cases, controls, and family-based samples assembled for previous genome-wide PGC mega-analyses of individual-level data. Cases and controls were not related.
  • For family-based samples, alleles transmitted to affected offspring (trio cases) were matched with untransmitted alleles (pseudo-controls).
  • All patients were of European ancestry and met criteria from the DSM Third Edition-Revised or Fourth Edition for the primary disorder of interest.

Results: SNPs at four loci surpassed the cutoff for genome-wide significance (P<5×10[–8]) in the primary analysis: regions on chromosomes 3p21 and 10q24, and SNPs within two L-type voltage-gated calcium-channel subunits, CACNA1C and CACNB2. Model selection analysis supported effects of these loci for several disorders. Loci previously associated with bipolar disorder or schizophrenia had variable diagnostic specificity. Polygenic risk scores showed cross-disorder associations, notably between adult-onset disorders. Pathway analysis supported a role for calcium-channel signaling genes for all five disorders.

Conclusions: Specific SNPs are associated with a range of psychiatric disorders of childhood onset or adult onset. In particular, variation in calcium-channel activity genes seems to have pleiotropic effects on psychopathology. These results provide evidence relevant to the goal of moving beyond descriptive syndromes in psychiatry, and toward a nosology informed by disease cause.

Clinical Commentary
This study suggests that there are risk genes for the five major mental illnesses that are common across diagnoses, suggesting that a common pathology exists across disorders. This supports the goal of moving beyond descriptive syndromes in psychiatry and toward a nosology informed by disease cause. The study specifically supports the notion that voltage-gated calcium-channel signaling may be a contributor to the pathogenesis of several psychiatric disorders, and supports this pathway as a potential therapeutic target for psychiatric illness.



Maintenance Treatment with Quetiapine when Combined with Either Lithium or Divalproex in Bipolar I Disorder: Analysis of Two Large Randomized, Placebo-Controlled Trials 

Suppes T, Vieta E, Gustaffson U, et al
Depress Anxiety. 2013 Jun 12. doi: 10.1002/da.22136. [Epub ahead of print]


Objectives: To determine the efficacy and safety of maintenance treatment with quetiapine combined with lithium or divalproex for preventing mood events in patients with bipolar I disorder.


  • Post-hoc analysis of pooled data from two identically designed, multicenter, double-blind, placebo-controlled, randomized trials of quetiapine in combination with lithium or divalproex for the prevention of mood events in patients with bipolar I disorder treated for up to 104 weeks (study 126, N=706; study 127, N=628).
  • Pre-randomization phase of 12–36-week duration during which patients received acute open-label treatment with quetiapine plus either lithium or divalproex at the discretion of the investigators.
  • Quetiapine or placebo was substituted for open-label quetiapine at the rate of 100 mg every 2 days.
  • Lithium levels were maintained at 0.5–1.2 mEq/L and valproate levels at 50–125 μg/mL.
  • Subjects achieving clinical stability for at least 12 weeks in the pre-randomization phase qualified for entry into the randomization phase, up to 104 weeks or until the recurrence of a predefined mood event.
  • Stability was defined as Young Mania Rating Scale (YMRS) and Montgomery–Asberg Depression Rating Scale (MADRS) total scores of 12 or less for 4 consecutive visits over 12 weeks.


Results: Of 3,414 patients in the stabilization phase, 1,326 were randomized. In patients with bipolar I disorder previously stabilized on the combination of quetiapine and lithium, continuation of quetiapine with lithium significantly increased the time to recurrence of any mood event, resulting in a 68% reduction in the risk of recurrence compared with placebo and lithium (HR=0.32; 95% CI: 0.24, 0.44; P<.001). Similarly, in patients previously stabilized on the combination of quetiapine and divalproex, this combination significantly delayed time to recurrence of any mood event, lowering the recurrence risk by 72% when compared with placebo plus divalproex (HR=0.28; 95% CI: 0.21, 0.37; P<.001). Subjects co-treated with lithium (with quetiapine or placebo) had a higher recurrence of mania than those treated with divalproex, and in subjects with an index episode of mania, placebo plus lithium was associated with a significantly higher risk of recurrence of a mania event than placebo plus divalproex.

Conclusions: In patients with bipolar I disorder previously stabilized on quetiapine and lithium or divalproex, maintenance therapy with quetiapine significantly increased the time to recurrence of a mood event (mania or depression) versus placebo, regardless of whether it was combined with lithium or divalproex.

Clinical Commentary
This post-hoc analysis of the registration trials of adjunctive quetiapine for maintenance treatment to prevent mood episodes in bipolar I disorder confirms that quetiapine is superior to placebo when added to lithium or divalproex, in patients who are able to maintain clinical stability for at least 12 weeks.  The rapid rate at which placebo is substituted for quetiapine raises the question of placebo unblinding, biasing the results, especially since close reading of the study finds much higher rates of insomnia reported in the placebo group. That lithium-treated patients had higher rates of mania is not interpretable since subjects were put on the drug at the discretion of the investigators, suggesting that the lithium and divalproex groups are not similar.



Meta-Analysis of Naltrexone and Acamprosate for Treating Alcohol Use Disorders: When are These Medications Most Helpful?

Maisel NC, Blodgett JC, Wilbourne PL, et al
Addiction. 2013;108(2):275-293.


Objectives: To determine when naltrexone and acamprosate are most helpful in the treatment of alcohol dependence by testing: (i) the relative efficacy of each medication given its presumed mechanism of action (reducing heavy drinking versus fostering abstinence) and (ii) whether different ways of implementing each medication (required abstinence before treatment, detoxification before treatment, goal of treatment, length of treatment, dosage) moderate its effects.


  • Meta-analysis of randomized, placebo- controlled trials testing the efficacy of naltrexone or acamprosate in populations 18 years of age or older.
  • Outcome measures compared included abstinence or heavy drinking as outcomes.
  • Craving examined as a secondary outcome.
  • Overall effect sizes calculated using a mixed-effects model.

: Acamprosate had a significantly larger effect size than naltrexone on the maintenance of abstinence, and naltrexone had a larger effect size than acamprosate on the reduction of heavy drinking and craving. For naltrexone, requiring abstinence before the trial was associated with larger effect sizes for abstinence maintenance and reduced heavy drinking compared with placebo. For acamprosate, detoxification before medication administration was associated with better abstinence outcomes compared with placebo.

Conclusions: In treatment for alcohol use disorders, acamprosate has been found to be slightly more efficacious in promoting abstinence and naltrexone slightly more efficacious in reducing heavy drinking and craving. Detoxification before treatment or a longer period of required abstinence before treatment is associated with larger medication effects for acamprosate and naltrexone respectively. 

Clinical Commentary 
Naltrexone is much more widely prescribed for the treatment of alcohol use disorders than is acamprosate. This is in part due to the results of the COMBINE study, a large placebo-controlled comparative effectiveness study of naltrexone, acamprosate, and behavioral therapy, which found benefit for naltrexone but not for acamprosate. COMBINE did not require a significant period of abstinence prior to randomization.  This meta-analysis suggests that acamprosate indeed has benefit for alcohol use disorders, especially when studies require detoxification beforehand and when abstinence is the outcome measures. 



Overt Irritability/Anger in Unipolar Major Depressive Episodes: Past and Current Characteristics and Implications for Long-Term Course

Judd LL, Schettler PJ, Coryell W, et al
JAMA Psychiatry. 2013 Sep 11. doi: 10.1001/jamapsychiatry.2013.1957. [Epub ahead of print]


Objectives: To determine the prevalence of overtly expressed irritability/anger and its effect on intake presentation and the long-term course of major depressive disorder.


  • Naturalistically observed outcomes from the NIMH Collaborative Depression Study (CDS).
  • Subjects were patients enrolled at 5 academic medical centers (Boston, Massachusetts; Chicago, Illinois; Iowa City, Iowa; New York, New York; and St Louis, Missouri) from 1978 to 1981, who sought treatment for a major affective episode.
  • Participants were followed for up to 31 years.
  • Patients entering the CDS during a definite major depressive episode (MDE) with no prior history of bipolar disorder (type I or II) were selected for analysis.
  • Diagnoses at study intake were made using Research Diagnostic Criteria (RDC)10 based on Schedule for Affective Disorders and Schizophrenia (SADS) interviews.
  • The SADS items assess overtly expressed irritability, anger, or annoyance during 2 time periods—the worst week of the study intake MDE and the week prior to the SADS interview.
  • Those with irritability at intake were compared to those without irritability.
  • Outcome was time to remission/recovery from the study intake MDE and time to subsequent relapse.

: Overt irritability/anger was present in 292 of 536 participants with a unipolar MDE at study intake (54.5%). It was associated with significantly increased severity of depressive illness (Table). No association was found with increased suicidal ideation or behavior. Results were not explained by comorbidity or other manic spectrum symptoms.

Overt Irritability/Anger

Clinical Marker for Complicated Depressive Illness

Present in 54% of patients with a unipolar major depressive episode

Irritability/Anger during MDE associated with increased:

-       Depression severity

-       Duration of index depressive episode

-       Impulsivity

-       Chronic and severe course of illness

-       Lifetime comorbid substance abuse, anxiety disorder, antisocial personality disorder, and psychosocial impairment

-       Life dissatisfaction

-       Bipolar II disorder in relatives

Conclusions: Irritability/anger during MDEs is a highly prevalent clinical marker of a more severe, chronic, and complex depressive illness.

Clinical Commentary
Given the advent of DSM-V and its new “mixed specifier” for a major depressive episode, this study suggests that the course of illness for patients with irritability/anger, commonly thought of as a “bipolar” symptom, is worse in patients with MDD. Given the new specifier, we await trials that prospectively examine treatments for patients with such symptoms.



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