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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 31, October 2014: Guest CommentatorOliver Freudenreich, MD, FAPM, Medical Director, Massachusetts General Hospital Schizophrenia Program; Associate Professor, Harvard Medical School, Boston, Massachusetts


Comparative Effectiveness of Risperidone Long-Acting Injectable vs First-Generation Antipsychotic Long-Acting Injectables in Schizophrenia: Results From a Nationwide, Retrospective Inception Cohort Study

Nielsen J, Jensen SO, Friis RB, et al
Schizophrenia bulletin, 2014 [Epub ahead of print]


ObjectiveLong-acting injectable antipsychotics (LAIs) are effective in reducing the relapse rate in patients with schizophrenia.  LAI risperidone (RIS-LAI) is the most widely used second-generation LAI.  This study compared the effectiveness of RIS-LAI with other first-generation LAIs (FGA-LAIs).  


  • This was a nationwide, retrospective inception cohort study using data from the nation-wide Danish registers (1995 to 2009).
  • Study subjects were adults with a life-time diagnosis of schizophrenia (ICD-10 diagnosed) who initiated a LAI during the study period.  The study examined the use of LAI in outpatient settings.
  • The primary outcome was time to psychiatric hospitalization using Cox-regression adjusting for relevant covariates.
  • Secondary outcomes included time to all-cause discontinuation and psychiatric hospitalization in patients without LAI possession gap >28 days, and number of bed-days after psychiatric hospitalization.


  • Among 4532 patients followed for 2700 patient-years, 2078 initiated RIS-LAI 45.9%) and 2454 initiated a FGA-LAI (54.1%).  The breakdown of FGA-LAIs was as follows: zuclopenthixol decanoate = 52.2%, perphenazine decanoate = 37.2%, haloperidol decanoate = 5.0%, flupenthixol decanoate = 4.4%, fluphenazine decanoate = 1.3%.
  • RIS-LAI was similar to FGA-LAIs regarding time to hospitalization (RIS-LAI = 246.2±323.7 days vs FGA-LAIs = 276.6±383.3 days; HR = 0.95, 95% confidence interval (CI) = 0.87-1.03, P = 0.199) and time to all-cause discontinuation (RIS-LAI = 245.8±324.0 days vs FGA-LAIs = 287.0±390.9 days; HR = 0.93, 95% CI = 0.86-1.02, P = 0.116).
  • In patients without LAI discontinuation, RIS-LAI and FGA-LAIs did not differ regarding time to hospitalization (RIS-LAI = 175.0±268.1 days vs FGA-LAIs = 210.7±325.3 days; HR = 0.95, 95% CI = 0.86-1.04, P = 0.254).
  • Duration of hospitalization was also similar (incidence rate ratio = 0.97, 95% CI = 0.78-1.19, P = 0.744).

Conclusion: In this nationwide cohort database study, RIS-LAI was not superior to FGA-LAIs regarding time to psychiatric hospitalization, all-cause discontinuation, and duration of hospitalization. Given the cost of hospitalization and second-generation antipsychotic (SGA)-LAIs, these findings require consideration when making treatment choices, but also need to be balanced with the individual relevance of adverse effects/patient centered outcomes. In the future, head-to-head trials and additional nationwide database studies including other SGA-LAIs are needed.


Clinical Commentary: This study nicely complements the findings from a recent randomized trial in the US that compared LAI paliperidone with LAI haloperidol (McEvoy JP, Byerly M, Hamer RM, et al: Effectiveness of paliperidone palmitate vs haloperidol decanoate for maintenance treatment of schizophrenia: a randomized clinical trial, JAMA 311(19):1978-1987, 2014).  Like the database study, no efficacy advantage for the much more expensive second-generation LAI was found by McEvoy et al.  However, there were expectable differences in side effects: LAI haloperidol caused more extrapyramidal side effects; LAI paliperidone caused more weight gain and larger prolactin elevation.  Given that FGAs are not a monolithic class, one wonders how a carefully dosed mid-potency LAI (e.g., LAI perphenazine) would perform in a head-to-head comparison against a SGA-LAI with regards to extrapyramidal side effects and weight gain.  That said, the combined results of the Danish trial and the recent US trial questions the preferred use of a second-generation LAI over a first-generation LAI.  As an aside, only 2 FGA-LAIs which are high-potency antipsychotics are available in the US; both constituted a small group of patients in the Danish study. 


Electroconvulsive Therapy Augmentation in Clozapine-Resistant Schizophrenia: A Prospective, Randomized Study

Petrides G, Malur C, Braga RJ, et al
The American journal of psychiatry, 2014 [Epub ahead of print]


Objective: Up to 70% of patients with treatment-resistant schizophrenia do not respond well to clozapine which is a dilemma for clinicians.   Pharmacological augmentation to clozapine has been studied with unimpressive results.  In the first prospective study with masked rater assessments, the authors examined the use of ECT as an augmentation to clozapine for treatment-refractory schizophrenia.



  • This was a randomized, 8-week treatment study with blinded assessment for clozapine-resistent schizophrenia patients.
  • Clozapine non-response was defined as a history of persistence of psychosis after at least 12 weeks of clozapine at a blood level of at least 350 ng/mL.
  • In order to be included, patients had to also have at least a core psychotic symptom of moderate severity and no prominent depressive symptoms.
  • Eligible patients were assigned to 8 weeks of treatment as usual (clozapine group) or an 8-week course of bilateral ECT plus clozapine (ECT plus clozapine group).
  • Nonresponders from the clozapine group received an 8-week open trial of ECT (crossover phase).
  • ECT was performed three times per week for the first 4 weeks and twice weekly for the last 4 weeks. Clozapine dosages remained constant.
  • The primary outcome variable was response rate.  Response was defined as ≥40% reduction in symptoms based on the psychotic symptom subscale of the Brief Psychiatric Rating Scale (BRPS), a Clinical Global Impressions (CGI)-severity rating <3, and a CGI-improvement rating ≤2.
  • To enhance rater blinding, the initial and final BPRS assessments were videotaped.



  • The intent-to-treat sample included 39 participants (ECT plus clozapine group, N=20; clozapine group, N=19).  All were inpatients.
  • All 19 patients from the clozapine group received ECT in the crossover phase.
  • Fifty percent of the ECT plus clozapine patients met the response criterion. None of the patients in the clozapine group met the criterion. In the crossover phase, response was 47%.  Those are striking results given the refractoriness of the patient group.
  • There were no discernible differences between groups on global cognition. Two patients required the postponement of an ECT session because of mild confusion.  Speed of processing was adversely affected by ECT when measured shortly after finishing the course of ECT.

Conclusion: The augmentation of clozapine with ECT was generally safe and effective.  Further research is required to determine 1) the persistence of the improvement, 2) the potential need for maintenance ECT, and 3) the best ECT regimen to minimize cognitive effects and seizures (which were not observed in this trial).

Clinical Commentary: This study examines an important clinical question: what can you do if a patient with schizophrenia is refractory to clozapine?  The usual approach that clinicians take is adding a second antipsychotic or a mood stabilizer.  Unfortunately, such combination treatments lead to polypharmacy but rarely if ever to clear-cut clinical improvement.  In this short-term study, ECT was offered to augment clozapine with very impressive results.  It remains to be seen how best to combine ECT with clozapine for maintenance treatment to minimize cognitive side effect while not losing efficacy.  This study suggests that a high-quality psychiatric treatment system would be characterized by the ability to provide ECT combined with clozapine for every patient who does not satisfactorily respond to clozapine.  I also wonder what effect ECT alone (acute followed by maintenance treatment) would have in a population that by definition was nonresponsive to clozapine.


Aripiprazole once-monthly for treatment of schizophrenia: double-blind, randomised, non-inferiority study

Fleischhacker WW, Sanchez R, Perry PP, et al
Br J Psychiatry, 2014 [Epub ahead of print]


ObjectiveLong-acting injectable antipsychotics (LAIs) are a good treatment choice for patients with schizophrenia who need maintenance therapy.  The FDA approval of LAI aripiprazole in 2013 was a welcome addition to the pharmacological armamentarium.  This study sought to establish at least equal efficacy for the prevention of relapse with the LAI form of aripiprazole given monthly compared to the oral, daily administration (where efficacy has been established).


  • This was a multi-site (105 centers world-wide) non-inferiority study.
  • Eligible patients had to have a diagnosis of schizophrenia for at least 3 years; had to be between 18 and 60 years of age; and they had to be responsive to antipsychotics other than clozapine.
  • 662 patients were randomized to enter an 38-weeks treatment phase during which they received double-blind treatment with monthly LAI aripiprazole 400 mg; oral aripiprazole (10 to 30 mg per day); or monthly LAI aripiprazole 50 mg.  The last, active-control arm which used a dose that is usually not effective was included to confirm assay sensitivity.
  • Prior to randomization, patients were switched to oral aripiprazole in a first switch stage (patients already on aripiprazole could participate as well).  Only patients who were found stable on oral aripiprazole during a stabilization phase were entered into the subsequent randomization phase.
  • All patients received injections and oral pills.
  • The main outcome variable was the Kaplan-Meier estimated impending relapse rate at week 26.  Of note, this variable was modified during the trial (reduced time period from 38 to 26 weeks) because of a very low relapse rate.  Relapse used a composite measure including hospitalization and worsening psychopathology.


  • Kaplan-Meier estimated impending relapse rates at week 26 were 7.12% for aripiprazole once-monthly 400 mg and 7.76% for oral aripiprazole.
  • This difference (-0.64%, 95% CI -5.26 to 3.99) excluded the predefined non-inferiority margin of 11.5%.
  • Treatments were superior to aripiprazole once-monthly 50 mg (21.80%, P⩽0.001).
  • A statistically significant (but probably not clinically significant) improvement in psychopathology with LAI aripiprazole compared to oral aripiprazole was observed.
  • The observed relapse rate in this trial was very low.
  • The observed side effects were consistent with the clinical experience with oral aripiprazole.

ConclusionAripiprazole once-monthly LAI at a dose of 400 mg was at least as effective as oral aripiprazole (i.e., it was “non-inferior”) for the prevention of relapse in schizophrenia.

Clinical CommentaryThere were no surprises in this clinical trial that establishes LAI aripiprazole as an effective alternative for patients who respond to oral aripiprazole and who want to switch to the long-acting version.  While not tested in this trial, LAI aripiprazole can be a good clinical choice for patients taking LAI antipsychotics but who might benefit from a switch to aripiprazole because of its relatively good metabolic profile.


Treatment of major depressive disorder using botulinum toxin a: a 24-week randomized, double-blind, placebo-controlled study

Magid M, Reichenberg JS, Poth PE, et al 
The Journal of clinical psychiatry, 2014 [Epub ahead of print]


ObjectivePreliminary work in 2 double-blind trials has shown that an essentially cosmetic procedure, botulinum toxin A (marketed as Botox) injections into the frown muscles of the forehead in patients with depression can improve depressive symptoms.  This study expands on this observation by expanding the time frame to 24 weeks which is longer than the neuromuscular effects of Botox (12 to 16 weeks).


  • This was a randomized, double-blind, placebo-controlled cross-over trial that lasted 24 weeks.  Participants received either one Botox injection (BTA) at time point 0, followed by one placebo injection at time point week 12 (BTA-first group) or first a placebo injection followed by Botox (BTA-second group).
  • 30 psychiatric outpatients recruited and randomized.  Patients who were mostly interested in the cosmetic effects of the treatment were not included.  Almost all study participants (93%) were women.
  • All patients had a diagnosis of major depressive disorder (DSM-IV) that was confirmed by a psychiatrist using a structured clinical interview.  Only patients in a current depressive episode and Hamilton Depression Rating Scale score (21-item HDRS-21) of 14 or greater were included.  Also, patients had to be able to produce “moderate-to-severe frown lines” as determined by a 10-point scale.
  • The same psychiatrist rated the patient’s depression throughout the study.  However, blinding was achieved by having the patient wear surgical caps that concealed the forehead.
  • The primary end point of the study was a change in HDRS-21 score at week 6 after injection, using response (at least 50% score reduction) as the main outcome.  The Beck Depression Inventory (BDI) was used as a subjective secondary measure.


  • Patients who received Botox (at either time point) showed a robust response that was statistically significant whereas placebo injections had essentially no effect.
  • Even though the cosmetic effects wore off at 12 and 16 weeks, improvement continued for those patients who had received BTA first.
  • Here are the response details:  HDRS-21 response rates were 55% (6/11) in the BTA-first group, 24% (4/17) in the BTA-second group, and 0% (0/19) in the placebo group (P < .0001). HDRS-21 remission rates (score ≤ 7) were 18% (2/11), 18% (3/17), and 0% (0/19), respectively (P = .057). HDRS-21 scores dropped -46% and -35% in the BTA-first and -second groups versus -2% in the placebo group (P < .0001). The BDI response rate (≥ 50% reduction from baseline) was 45% (5/11) in the BTA-first group, 33% (6/18) in the BTA-second group, and 5% (1/19) in the placebo group (P = .0067). BDI remission rates (score ≤ 9) were 27% (3/11), 33% (6/18), and 5% (1/19), respectively (P = .09). BDI scores dropped -42% and -35% in the BTA-first and -second groups versus -15% in the placebo group (P < .0001).
  • The placebo effect was rather small.

ConclusionBotox injections in the glabellar (forehead) region can improve depressive symptoms.  The treatment is safe.

Clinical Commentary: At first glance perhaps surprising, the efficacy of Botox injections for depression becomes understandable when viewed in the light of the James-Lange theory of emotions.  James and Lange proposed that subjective feelings of depression follow the outward bodily expressions of depression.  Having a sad frown on your face makes you feel sad, not the other way around.  Botox seems to work by inhibiting the muscles responsible for a sad face which according to this theory prevents the development of feeling depressed.  Secondarily, patients by simply appearing less depressed might benefit from more positive feedback they elicit from their peers.  This study shows that the effect is not merely driven by the cosmetic effects of Botox as the antidepressive effects outlasted any cosmetic effects.  I don’t know if Botox injections will ever become the mainstay of clinical treatment for depression but its simplicity and effectiveness is intriguing.  More work is needed to select the best patients for the procedure (e.g., needed baseline muscle activity to produce frown lines) and the optimal duration of treatment. 


Effect of adjunctive L-methylfolate 15 mg among inadequate responders to SSRIs in depressed patients who were stratified by biomarker levels and genotype: results from a randomized clinical trial

Papakostas GI, Shelton RC, Zajecka JM, et al
The Journal of clinical psychiatry, 2014 [Epub ahead of print]


ObjectiveThe majority of patients with major depressive disorder do not achieve complete symptomatic remission from antidepressants, likely because of etiological and pathophysiological heterogeneity.  Identifying clinical subtypes of depression (based on genetic and biological markers) that might preferentially respond to a particular treatment is a high priority.  This study evaluated the effect of specific biological and genetic markers on the antidepressant efficacy of adjunctive L-methylfolate 15 mg versus placebo using data from a previous clinical trial of inadequate responders to selective serotonin reuptake inhibitors (SSRIs).


  • This was a post hoc analysis of two previously reported double-blind, randomized, placebo-controlled trials that used the sequential parallel comparison design (Papakostas GI, Shelton RC, Zajecka JM, et al: L-methylfolate as adjunctive therapy for SSRI-resistant major depression: results of two randomized, double-blind, parallel-sequential trials, Am J Psychiatry 169(12):1267-1274, 2012).
  • Psychiatric outpatients with SSRI-resistant MDD (DSM-IV criteria) received L-methylfolate 15 mg/d for 60 days, placebo for 30 days followed by L-methylfolate 15 mg/d for 30 days, or placebo for 60 days.
  • The effects of baseline levels of select biological and genetic markers individually and combined on treatment response to L-methylfolate versus placebo were evaluated.
  • The primary outcome variable was the effect of biomarkers on the response on the 28-Item Hamilton Depression Rating Scale (HDRS-28).
  • Biological markers included high-sensitivity C-reactive protein (hsCRP), body mass index (BMI), the S-adenosylmethionine/S-adenosylhomocysteine ratio (SAM/SAH ratio), and 4-hydroxy-2-nonenal (4-HNE) level in addition to molecular polymorphisms of genes implicated in folate metabolism, among others.
  • The study was conducted over a 2-year period from 2009 to 2011.


  • Seventy-five patients were enrolled.
  • Patients with specific biological (body mass index ≥ 30 kg/m², elevated hsCRP or 4-HNE, low SAM/SAH ratio and genetic markers at baseline) had significantly (P ≤ .05) greater pooled mean change from baseline on the HDRS-28 with L-methylfolate versus placebo.
  • Pooled mean change from baseline on the Clinical Global Impressions-Severity of Illness scale was significantly (P < .05) greater with L-methylfolate versus placebo for most genetic markers.
  • Most combinations of baseline biological and genetic markers predicted significantly (P ≤ .05) greater reductions in pooled mean change from baseline in HDRS-28 scores with L-methylfolate versus placebo.

ConclusionBiomarkers associated with inflammation or metabolism and genomic markers associated with L-methylfolate synthesis and metabolism may identify patients with SSRI-resistant depression who are responsive to adjunctive therapy with L-methylfolate 15 mg. Confirmatory studies are needed to examine the effects of patient stratification based on inflammatory or genetic markers.

Clinical Commentary: This study is a good example of personalized medicine in which patients are selected for specific treatments based on genetic or biological characteristics in order to improve treatment response.  While not yet routine in psychiatry, this approach is the norm in other branches of medicine (e.g., oncology).  This study suggests that 15 mg L-methylfolate added to depression treatment with SSRIs can benefit some patients, particularly those who are obese and those with increased inflammatory markers and certain genotypes.  Clinically, one could either use L-methylfolate in any patient with only a partial treatment response or pre-select patients for added L-methylfolate from the beginning of treatment by measuring hsCRP.  Trying to capture a patient’s inflammatory status with hsCRP might be particularly promising as treatment resistance is increasingly tied to the presence of a low-grade inflammatory state.


Monitoring for metabolic side effects among outpatients with dementia receiving antipsychotics

Mittal D, Li C, Viverito K, et al 
Psychiatric services 65(9):1147-1153, 2014


ObjectiveWhen clinicians use second generation antipsychotics, guidelines recommend metabolic monitoring.  In patients with schizophrenia, guideline-concordant monitoring rates have remained low.  This study examines metabolic monitoring in older outpatients with dementia who were started on a new antipsychotic.


  • This was a retrospective cohort study using the VA system database.
  • Data were extracted for 3,903 elderly (i.e., age 60 or above) outpatients with dementia but without a psychotic disorder as well as a comparison group of psychotic patients without dementia.
  • Propensity-score matching was used to compare the groups to account for the expectable differences in patient characteristics in the two groups.  The final sample included 1,576 matched pairs.
  • Using the 2004 American Diabetes Association and American Psychiatric Association Expert Consensus Recommendations, the authors operationalized observed monitoring rates as having obtained weight, plasma glucose or HbA1c, and LDL cholesterol within 30 days before or after starting the antipsychotic.  The recommended 3-month follow-up was operationalized as between 60 and 120 days after starting the antipsychotic.


  • For both groups, monitoring rates were low at baseline and even lower at the 3-month follow-up.
  • At baseline, 68% of the matched dementia patients were weighed, compared with 63.7% of the matched psychosis patients (odds ratio [OR]=1.28, 95% confidence interval [CI]=1.03-1.48).
  • Monitoring for glucose or HbA1c and LDL cholesterol was not significantly different between the groups: glucose or HbA1c, 41% versus 44%; LDL, 24% versus 27%.
  • At three months, metabolic monitoring for all three parameters was significantly lower for the dementia group: weight, OR=.86, CI=.75-.99; glucose or HbA1c, OR=.83, CI=.71-.97; and LDL, OR=.69, CI=.57-.85.

Conclusion: Monitoring rates for metabolic side effects from antipsychotics were low for both elderly patients with dementia and for patients with psychosis.  Dementia patients had lower rates at follow-up compared to psychosis patients.

Clinical CommentaryWhile there is concern about the use of antipsychotics in elderly patients with dementia (i.e., safety as well as questionable efficacy), clinicians who lack better choices will continue to use antipsychotics in patients with dementia who exhibit behavioral problems.  This study is a reminder that guidelines recommend metabolic monitoring for any (i.e., not just schizophrenia) patient that is starting a second generation antipsychotics.  In already frail elderly with a propensity towards diabetes, monitoring might be particularly important.  Clinic administrators should develop monitoring systems and workflows that assure appropriate monitoring for all elderly patients who are taking antipsychotics, regardless of diagnostic indication.


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