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Issue 44, Dec 2015
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Another antipsychotic shown to work for bipolar depression


Durgam et al. An 8-Week Randomized, Double-Blind, Placebo-Controlled Evaluation of the Safety and Efficacy of Cariprazine in Patients With Bipolar I Depression. Am J Psychiatry. 2015 Nov 6:appiajp201515020164. [Epub ahead of print] PubMed PMID: 26541814.

  • Bipolar depression remains one of the more challenging mental health disorders to treat.
  • Second-generation antipsychotics have been shown to work for treating bipolar disorder.
  • However, only some second-generation antipsychotics have been shown to work for bipolar depression.
  • Clinical trials of some other second-generation antipsychotics for bipolar depression were negative. In fact, quetiapine and lurasidone are the only antipsychotics approved by the United States Food and Drug Administration (FDA) for the treatment of bipolar depression.
  • Cariprazine (brand name Vraylar) is a second-generation antipsychotic that was recently approved by the FDA for the treatment of schizophrenia and for the acute treatment of manic or mixed episodes associated with bipolar I disorder.
  • For commentary on studies of cariprazine for the treatment of schizophrenia and of manic/mixed episodes of bipolar I disorder, see (the link will open in a new window).
  • Note: Cariprazine is not approved by the FDA for the treatment of bipolar depression and, therefore, the study discussed below evaluates a potential off-label use of cariprazine.
  • Aim: to evaluate the efficacy, safety, and tolerability of cariprazine for the treatment of acute bipolar I depression in adults.
  • This was a multinational, multicenter study.
  • A randomized, double-blind, placebo-controlled design was used.
  • Adults with bipolar I disorder, currently experiencing a depressive episode were enrolled.
  • The participants were randomized to 8 weeks of treatment with one of the following:
    1. . Cariprazine 0.75 mg/day
    2. . Cariprazine 1.5 mg/day
    3. . Cariprazine 3.0 mg/day
    4. . Placebo
  • Note: The FDA-approved dose of cariprazine for schizophrenia is 1.5 to 6 mg/day and for bipolar mania is 3 to 6 mg/day. So, this study used doses of cariprazine that were on the low side.
  • A total of 571 patients were included.
  • Those who received cariprazine 0.75 mg/day did not show a statistically significant reduction in depression compared to placebo.
  • Compared to those who received placebo, patients who received cariprazine 1.5 mg/day showed greater reduction in the severity of depression as measured by the Montgomery-Asberg Depression Rating Scale.
  • Those who received cariprazine 3 mg/day showed greater reduction in the Montgomery-Asberg Depression Rating Scale than those who received placebo. However, when correction was made for multiple statistical tests being done (multiple comparisons), the difference was not statistically significant. What this means is there was an apparent difference between the two groups but we cannot rule out the possibility that it could also have just been due to chance.
  • Similarly, on the Clinical Global Impression-Severity scale ( too, 1.5 mg/day of cariprazine was more efficacious than placebo. Again, the 3 mg/day showed greater improvement than placebo but this was not statistically significant when adjusted for multiple comparisons.
  • When analyzed by a different but commonly used statistical approach, all three doses of cariprazine were statistically significantly more efficacious than placebo.
  • Now, to get an idea of how clinically significant the effects may be, as usual let's look at the proportion of patients who were "Responders," i.e., had a 50% or greater reduction in MADRS score:

    Placebo 32%
    Cariprazine 0.75 mg/day 39%
    Cariprazine 1.5 mg/day 50% (statistically significantly > placebo)
    Cariprazine 3 mg/day 45%
  • Generally, a 10% or greater difference in response rates between a medication and placebo is considered clinically useful and a 20% or greater difference is considered a very strong effect. Here, the drug-placebo difference for cariprazine 1.5 mg/day was 18%, indicated a clinically useful effect.
  • As usual, I will define adverse events as those occurring in 5% or more of patients and at least twice as often as on placebo. Only two adverse events met this definition:


Adverse EventPlaceboCariprazine 0.75 mg/dayCariprazine 1.5 mg/dayCariprazine 3.0 mg/day
  • Cariprazine 1.5 mg/day was efficacious for the treatment of bipolar I depression.
Clinical Commentary
  • We definitely need more options for the treatment of bipolar depression, so cariprazine is a welcome addition for that purpose.
  • The exact dose to use is not clear yet, but it seems that a relatively low dose may be enough.
  • Currently, Vraylar is available only in 1.5 mg, 3 mg, 4.5 mg, and 6 mg strengths. Therefore, starting at 0.75 mg is not an option. Perhaps, if it is approved in the future by the FDA for the treatment of bipolar depression, the manufacturer may make a lower dose strength available.
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Long-acting antipsychotic after a first episode of schizophrenia?


Subotnik et al. Long-Acting Injectable Risperidone for Relapse Prevention and Control of Breakthrough Symptoms After a Recent First Episode of Schizophrenia. A Randomized Clinical Trial. JAMA Psychiatry. 2015 Aug;72(8):822-9. PubMed PMID: 26107752.

  • Non-adherence to medication is the number one problem in the treatment of schizophrenia (and other chronic diseases).
  • There is no doubt in my mind that long-acting antipsychotics should be used much more often than they currently are.
  • But usually we think of using long-acting antipsychotics in persons with schizophrenia that is chronic and after they have had poor adherence to oral antipsychotic.
  • A colleague alerted me to this article and told me that it had changed her practice. She had now used long-acting antipsychotic medication in many of her patients with first-episode psychosis and has had good results.
  • Long-acting antipsychotic medications are rarely used following a first episode of schizophrenia.
  • Previous studies of second-generation long-acting antipsychotics have, surprisingly, not found them to be clearly better than oral antipsychotic. The reasons for this could include:

    a) use later in the course of illness

    b) failure to compare the same second-generation antipsychotic in oral and long-acting injectable form.
  • Aim: To compare the clinical efficacy of the long-acting injectable formulation of risperidone with the oral formulation in the early course of schizophrenia.
  • A randomized, controlled clinical trial was conducted. But the raters were not blinded.
  • The setting was a university-based research clinic.
  • Eighty-six patients with recent onset of schizophrenia were recruited.
  • Patients with recent active substance abuse that may have triggered the psychotic symptoms were excluded.
  • Subjects received either long-acting injectable risperidone or oral risperidone for 12 months.
  • Because this was part of a bigger study, half of each group was also randomized to receive cognitive remediation to improve cognitive functioning or healthy-behaviors training to improve lifestyle habits and well-being.
  • Thus, frequent clinic visits, case management, and enriched psychosocial treatment were included, which probably had an effect on outcomes.
  • 86 patients were randomized but 3 then refused treatment with the long-acting injectable risperidone.
  • The rate of psychotic exacerbation and/or relapse was lower in those who received the long-acting risperidone (5%) compared with those who received oral risperidone (33%).
  • 5% versus 33%! That’s a big difference!
  • On a symptom level, there was statistically significantly greater control of hallucinations and delusions in patients who received long-acting injectable risperidone.
  • The cognitive remediation versus healthy-behaviors training made no difference.
  • Adherence was better in the long-acting risperidone group compared to the oral risperidone group.
  • As one would expect, medication adherence was statistically related to reduced exacerbation/relapse and to control of breakthrough psychotic symptoms.
  • Long-acting injectable risperidone did not have any more adverse effects than oral risperidone.
  • Use of long-acting injectable risperidone after a first episode of schizophrenia was more efficacious than oral risperidone.
Clinical Commentary
  • An important limitation of this study is that the raters were not blinded to the treatment.
  • I think that exclusion of persons with more active substance use and provision of intensive psychosocial services could have improved adherence in patients who received oral risperidone. That is, in my opinion, long-acting injectable antipsychotic may be even more useful when such support is not available and when non-adherence to oral medication is more likely.
  • It could be that the key point from this study is that intervening early in the illness leads to better results.
  • If you think about it, there is no reason to not use long-acting injectable antipsychotics even after the first episode. Rather, with better adherence and better outcomes after the first episode, maybe the long-term course of the illness could be changed for the better? 
  • I think that we are (or should be) now entering a new era in that the use of long-acting, injectable second-generation antipsychotics will be become more and more common.
  • Why? Because now we have:

    1. Multiple such formulations of second-generation antipsychotics.

    2. Formulations that are more convenient --- don't require refrigeration, come in a single dose syringe rather than requiring reconstitution in a vial.

    3. Formulations that can be given once a month or once every three months rather than every two weeks.
  • On the other hand, we must remember that use of long-acting, injectable antipsychotic is not a panacea. Ultimately, it too only works if the patient continues to receive the injection.
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A non-opioid maintenance treatment for opioid use disorder


Kowalczyk et al. Clonidine Maintenance Prolongs Opioid Abstinence and Decouples Stress From Craving in Daily Life: A Randomized Controlled Trial With Ecological Momentary Assessment. Am J Psychiatry. 2015 Aug 1;172(8):760-7. PubMed PMID: 25783757.

  • We continue to struggle to help persons with substance use disorders. Maintaining abstinence is the biggest challenge. Any medication that could help with that would be welcome.
  • A rat model of relapse into opioid use suggested the potential use of clonidine for maintenance of abstinence.
  • Human studies have suggested that alpha-2 agonists like clonidine reduce craving for opioids -- both craving induced by stress and that which is cue-related.
  • Aims:

    1. To evaluate whether clonidine reduces relapse into opioid use
    2. To test the hypothesis that clonidine helps by reducing craving induced by stress.
  • This was a randomized, double-blind, placebo-controlled clinical trial.
  • 208 patients who were dependent on opioids were recruited from an outpatient buprenorphine clinic. Of these, 118 were abstinent at both week 5 and week 6. 
  • It makes sense to only include persons who were able to achieve short-term abstinence because the mechanisms of short-term abstinence and longer-term maintenance are probably different.
  • So, these 118 patients were then randomized to receive either clonidine or placebo for 14 weeks.
  • Clonidine was titrated up: 0.1 mg/day for one week, then 0.2 mg/day for one week, then 0.3 mg/day. The dose needed to be reduced in a few patients.
  • Participants came to the clinic 7 days a week and received individual counseling once a week.
  • Sublingual buprenorphine 8 to 24 mg/day was continued.
  • A urine drug screen (UDS) was done thrice a week.
  • The outcome measures were "Lapse" and "Relapse."
  • Lapse: every time a urine drug screen was either positive for opioids or was missed.
  • Relapse: two or more consecutive lapses.
  • Daily stress and craving were recorded at 4 random times each day by using hand held devices.
    • The mean number of consecutive days of abstinence from opioids was 35 days for persons who received clonidine and 26 days for those who received placebo.
    • Persons who received clonidine had longer times before a Lapse compared to persons who received placebo.
    • There was no difference between persons who received clonidine or placebo in terms of time to Relapse.
    • In patients who received clonidine, craving was less likely to be related to stress ratings. 
    • On the other hand, cue-related cravings (on seeing the drug) were not different between patients who received clonidine or placebo.
    • Adverse events
Adverse EventClonidinePlacebo
Dry mouth10%0%
  • One patient who was dehydrated developed "symptomatic bradycardia."
  • Clonidine is useful not only in opioid withdrawal but also as an adjunct in maintenance treatment.
  • Even when physical withdrawal is no longer an issue, continuation of clonidine seems to reduce craving associated with feeling stressed.
Clinical Commentary
  • This is a very interesting study. If its findings are confirmed in another, larger clinical trial, use of clonidine for maintenance treatment could become common in clinical practice. However, at this time we must wait for a replication study before adopting the buprenorphine-clonidine combination into routine clinical practice.
  • My own thought is that these patients need all the help they can get. Since they are relapsing even with multiple types of treatment, it is probably best to use a "belt and suspenders" approach. That is, consider using both buprenorphine and clonidine? (Note: such use would be off label.)
  • I think the key piece of information we need is: which patients are most likely to benefit from addition of clonidine? For now, it seems that it would be those who report that their craving and likelihood of relapse are related to feeling stressed rather than to being exposed to cues associated with the drug.
  • Of course, we will have to keep in mind potential side effects of clonidine, monitor patients closely, and balance risk against potential benefit.
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Which disorders does psychodynamic psychotherapy work for?


Leichsenring et al. The empirical status of psychodynamic psychotherapy - an update: Bambi's alive and kicking. Psychother Psychosom. 2015;84(3):129-48. PubMed PMID: 25833321.

  • While practice guidelines emphasize cognitive-behavior therapy, psychodynamic therapy is often emphasized in psychiatry residency programs and is widely practiced, at least as part of an eclectic approach.
  • In discussions of “evidence-based psychotherapies,” psychodynamic psychotherapy is often excluded.
  • It is important, therefore, for both trainees and practitioners to have some understanding of the research support for psychodynamic therapy – where it exists and where it does not.
  • What qualifies as an evidence-based psychotherapy? Rigorous criteria for this have been proposed and improved upon. A key tenet of these criteria is that two randomized controlled trials showing efficacy are required for a treatment to be called “efficacious” and one randomized, controlled trial for it to be called “possibly efficacious”.
  • This paper applies these criteria to present an update on the evidence for psychodynamic therapy in specific mental disorders.
  • A systematic search of the literature was performed to identify relevant articles.
  • Criteria for including articles were ones where:
  1. A randomized, controlled trial evaluated psychodynamic therapy as a treatment for a specific problem in adults.
  2. Reliable and valid measures for diagnosis and outcome were used.
  3. Treatment manuals or manual-like guidelines were used to deliver the psychotherapy.
  4. Psychodynamic therapy was found to be either superior to no treatment/placebo/alternative treatment OR found to be equivalent to an established treatment.
  • A total of 39 randomized, controlled trials met the inclusion criteria.  
  • Psychodynamic therapy has been shown to be efficacious in:

    1. Major depressive disorder
    2. Social anxiety disorder
    3. Borderline personality disorder
    4. “Heterogeneous” personality disorders
    5. Somatoform pain disorder
    6. Anorexia nervosa 


  • For major depressive disorder, psychodynamic therapy has also been shown to be efficacious in combination with pharmacotherapy. 
  • For some disorders, only one RCT was found and, therefore, psychodynamic psychotherapy should be considered possibly efficacious but not definitely shown to be efficacious. These disorders were:

    1. Dysthymia
    2. Complicated grief
    3. Panic disorder
    4. Generalized anxiety disorder
    5. Substance abuse/dependence. 


  • Lastly, for some disorders, psychodynamic psychotherapy has not been shown in RCTs to be efficacious:

    1. Obsessive-compulsive disorder
    2. Posttraumatic stress disorder
    3. Bipolar disorder
    4. Schizophrenia spectrum disorders. 


  • No direct comparisons of psychodynamic therapy alone with pharmacotherapy alone are available. 
  • Evidence has emerged that psychodynamic therapy is efficacious or possibly efficacious in a wide range of common mental disorders. 
  • Further research is required for those disorders for which sufficient evidence does not yet exist.
Clinical Commentary
  • The authors note that there is a lot of overlap between interventions even when the psychotherapy is delivered in a manualized, i.e., standardized fashion. For example, cognitive-behavioral therapists use interpretations or clarifications as often as psychodynamic therapists. Similarly, psychodynamic therapists have been found to adhere to a CBT prototype to the same extend as they adhered to a psychodynamic prototype.
  • BUT, what is most important is not whether similar things are done in different types of psychotherapy but which of the interventions are associated with the benefit of the psychotherapy. In many studies, the psychodynamic interventions have been shown to be associated with the good outcome. Also, it has been found that changes in psychodynamically relevant mediators such as core conflicts or insight are significantly related to good outcomes.
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Why do we eat more sugar when under stress?

Tryon et al. Excessive Sugar Consumption May Be a Difficult Habit to Break: A View From the Brain and Body. J Clin Endocrinol Metab. 2015 Jun;100(6):2239-47. PubMed PMID: 25879513.

  • Obesity is a huge problem in society in general and in particular in persons with mental health problems.
  • Excessive consumption of sugar plays a key role in weight gain.
  • Also, many of our patients – especially those with atypical depression – report sugar cravings.
  • Thus, sugar cravings are of great interest to the mental health clinician.
  • Consuming sugar in response to being stressed is a habit that is difficult to break. But why?
  • Rodent studies suggest that sugar consumption may activate a negative feedback pathway that may turn off the stress response and thereby reinforce habitual sugar overconsumption.
  • Aim: To evaluate how consuming sugar affects response to stress.
  • This was a randomized, double-blind controlled clinical trial.
  • The study was conducted in a University setting.
  • Nineteen women (18- to 40-years-old) with a body mass index of 20 to 34 Kg/m2 were enrolled. (Note: normal BMI is 18.5 to 25 Kg/ m2)
  • For 2 weeks, these women consumed a beverage three times a day that contained either sucrose or aspartame. They were told not to consume any other sweetened beverages including fruit juices.
  • A stressful task – the Montreal Imaging Stress Task – was given.  Briefly, this involves doing timed mental arithmetic and the subject being socially evaluated.
  • Changes in salivary cortisol and in brain responses (on functional MRI) in response to the stressful task, were measured.
  • In addition, a naltrexone challenge was used. Increased nausea and rise in cortisol after taking naltrexone indicates weak opioid tone.
  • Sucrose consumption was associated with higher stress-induced increase in activity in the left hippocampus. Note: normally, stress reduces activity in the hippocampus.
  • Sucrose consumption for 2 weeks was associated with reduction in the stress-induced increase in cortisol.
  • The sucrose group also had a lower reactivity to naltrexone in the form of lower nausea, suggesting higher opioid activity in the brain. 
  • This is the first study to show that consumption of sugar but not artificial sweetener inhibits stress-induced cortisol secretion.
  • Also, consumption of sugar inhibited the usual stress-induced decrease in activity in the hippocampus and increased opioid tone in the brain.
  • It seems that there is a negative feedback pathway that is affected by sugar.
  • This may make explain why many persons are more likely to use sugar-containing foods and beverages when under stress.
Clinical Commentary
  • Knowing the strong biological basis for the reinforcing effects of sugar consumed under stress can make us more empathetic towards our patients (and ourselves!).
  • Attempts to reduce excessive sugar consumption and obesity must include stress reduction and stress management strategies.
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Rajnish Mago, MD
Associate Professor of Psychiatry, Thomas Jefferson University

GME Research Review is a monthly newsletter edited by Rajnish Mago, MD, who is Associate Professor of Psychiatry at Thomas Jefferson University and is author of "The Latest Antidepressants and Side Effects of Psychiatric Medications: Prevention, Assessment, and Management." Dr. Mago selects, summarizes, and provides a clinical commentary on the latest published research in psychiatry.

We are always carefully evaluating which research papers to discuss in GME Research Review. Have you come across a research paper published in the last 6 months that you think is clinically relevant? If you would like to ask Dr. Mago to consider analyzing it, please email him the citation at: [email protected]

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