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GME Research Review

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 come across a research paper published in the last 6 months that you thought is clinically relevant? Do you want me to analyze it for you and for the benefit of others? Please email me the citation at [email protected]


Issue 42, October 2015 

On September 17, 2015, the United States Food and Drug Administration (FDA) announced that it had approved cariprazine (Vraylar) for the treatment of schizophrenia and of bipolar disorder in adults. This approval was based on three Phase III clinical trials in each disorder. Three of these six trials have been published. It seems timely to review these three published studies.


Some background on cariprazine:

  • Cariprazine is a partial agonist at both dopamine D3 and D2 receptors.
  • Cariprazine is a partial agonist at D2 receptors like aripiprazole is, but it is different in that it has 10 times greater affinity for D3 receptors than for D2 receptors.
  • D2 receptors are heavily expressed in the brain regions associated with motor functions, whereas D3 receptors are more selectively expressed in the limbic region (the mesolimbic and mesocortical dopaminergic pathways), which are associated with cognition and emotion (Cho et al., 2010). It is hypothesized that blocking dopamine D2 receptors leads to antipsychotic efficacy while blocking D3 receptors may help with mood and cognition. Animal studies have reported pro-cognitive effects that were believed to be due to dopamine D3 preferring agents (Citrome, 2013).

 

Clinical trial of cariprazine for acute exacerbation of schizophrenia

Kane et al. Efficacy and Safety of Cariprazine in Acute Exacerbation of Schizophrenia: Results From an International, Phase III Clinical Trial. J Clin Psychopharmacol. 2015 Aug;35(4):367-73. PubMed PMID: 26075487.


Why is this study important?

  • Phase III studies are the larger, randomized controlled trials on the basis of which the efficacy, safety, and tolerability of a medication is assessed.
  • At least two positive phase III studies are required for FDA approval. Often, manufacturers will conduct more than two phase III studies for each indication because not every study will find drug to be more efficacious than placebo.
  • In the case of cariprazine’s approval for the treatment of acute exacerbation of schizophrenia, this is one of the three key RCTs conducted.
  • Cariprazine is a partial agonist at both dopamine D3 and D2 receptors.
  • Cariprazine is a partial agonist at D2 receptors like aripiprazole is, But it is different in that it has 10 times greater affinity for D3 receptors than for D2 receptors.
  • The hypothesis is that blocking dopamine D2 receptors leads to antipsychotic efficacy but blocking D3 receptors may help with mood and cognition.


Background

  • Aim: to evaluate the efficacy, safety, and tolerability of cariprazine in patients with acute exacerbation of schizophrenia.


Methods

  • Patients were randomized to six weeks of double-blind treatment with cariprazine 3 to 6 mg/day, cariprazine 6 to 9 mg/day, or placebo.
  • The predefined primary efficacy measure was the change from baseline to week 6 in the total score on the Positive and Negative Syndrome Scale (PANSS).


Results

  • The number of patients in each group were: cariprazine 3 to 6 mg/day, n = 151; cariprazine 6 to 9 mg/day, n = 148; and placebo, n = 147.
  • Keep in mind that the dose of cariprazine that the FDA approved for schizophrenia is 1.5 to 6 mg/day. Therefore, both the efficacy and the safety/tolerability data for the higher dose group are not relevant to usual clinical practice.
  • After six weeks of treatment, patients in both cariprazine groups showed statistically significantly greater reduction in total PANSS score than patients who received placebo.
  •  On the clinician rated Clinical Global Impressions-Severity scale too, both cariprazine groups showed statistically significantly greater reduction than patients who received placebo.
  • I have defined treatment-emergent adverse events here as those that occurred in ≥5% of patients in the cariprazine 3 to 6 mg/day group (since 6 mg/day is the maximum dose recommended by the FDA) and at least twice as often as on placebo. These were:

Adverse Effect

Placebo

Cariprazine

3 to 6 mg/day

Cariprazine

6 to 9 mg/day

Akathisia

3%

16%

17%

Extrapyramidal disorder

2%

5%

10%

Constipation

3%

9%

6%

Tremor

2%

7%

5%

Diarrhea

1%

5%

4%

 

Conclusions

  • Cariprazine is efficacious for schizophrenia and generally well tolerated.


Clinical Commentary

  • While cariprazine has been shown to be efficacious in this study, it is not possible from this data to draw any firm conclusions as to whether it has any advantages over other antipsychotics, e.g., in terms of negative symptoms.
  • There is another, unpublished study that found that cariprazine was superior to risperidone for the treatment of negative symptoms in patients with schizophrenia who presented with mainly negative symptoms.


Clinical trial of cariprazine for manic or mixed episodes of bipolar I disorder: the Sachs et al. study

Sachs et al. Cariprazine in the treatment of acute mania in bipolar I disorder: a double-blind, placebo-controlled, phase III trial. J Affect Disord. 2015 Mar 15;174:296-302. PubMed PMID: 25532076.


Why is this study important?

  • For the same reason as the above study – this and the next study discussed are two key phase III studies that demonstrated the efficacy of cariprazine for acute manic and mixed episodes of bipolar I disorder.


Background

  • Aim: This study aimed to assess the efficacy and safety/tolerability of cariprazine in patients with manic or mixed episodes of bipolar I disorder.


Methods

  • A randomized, double-blind, placebo-controlled study design was used.
  • Patients were randomized to 3 weeks of treatment with cariprazine flexible dose from 3 to 12mg/day (n=158) or placebo (n=154).
  • Note: the FDA approved dose of cariprazine for manic episodes is 3 to 6 mg/day (with a starting dose of 1.5 mg/day).
  • Note: when a study uses a flexible dose, it means that the treating clinician could adjust the dose within the range allowed. Here, the dose range allowed was a minimum of 3 mg/day and a maximum of 12 mg/day.
  • The primary efficacy parameter was change in the total score on the Young Mania Rating Scale (YMRS) from baseline to end of three weeks of treatment.


Results

  • Over the three weeks of treatment, patients who received cariprazine showed a statistically significantly greater reduction in YMRS scores than did patients who received placebo.
  • After starting treatment, the first assessment was done after four days of treatment. Even at that point, a statistically significant difference in the improvement on the YMRS total score was found between patients who were receiving cariprazine and those who were receiving placebo.
  • Cariprazine also showed greater efficacy than placebo on the Clinical Global Impression-Severity scale (CGI-S) and the Positive and Negative Syndrome Scale (PANSS).
  • What were the response rates (50% or greater improvement on the YMRS)? Cariprazine 59%, placebo 44%. As you know, a 10% or greater difference in response rates is generally considered a clinically meaningful effect.
  • What were the remission rates (YMRS total score of 12 or less)? Cariprazine 52%, placebo, 35%.
  • Common treatment-emergent adverse events (occurring in 5% or more of patients on cariprazine and at least twice as often as on placebo) were:

 

 

Placebo

Cariprazine

Akathisia

5%

22%

Extrapyramidal disorder

2%

15%

Tremor

4%

11%

Dyspepsia

3%

11%

Vomiting

4%

10%

Dizziness

4%

8%

Diarrhea

1%

7%

Somnolence

1%

6%

Restlessness

1%

6%

Pyrexia

2%

5%

 

Conclusions

  • Cariprazine flexible dose 3 to 12 mg/day was efficacious and generally well tolerated.


Clinical Commentary

  • Since cariprazine is a partial agonist at dopamine receptors, it will naturally be compared to aripiprazole.
  • While this study showed cariprazine to be efficacious, from this data it is not possible to say that it has any advantage over aripiprazole.

 

Clinical trial of cariprazine for manic or mixed episodes of bipolar I disorder: the Calabrese et al. study

Calabrese et al. Efficacy and safety of low- and high-dose cariprazine in acute and mixed mania associated with bipolar I disorder: a double-blind, placebo-controlled study. J Clin Psychiatry. 2015 Mar;76(3):284-92. PubMed PMID: 25562205.


Why is this study important?

  • For the same reason as the above study – this and the above study by Sachs et al. are two key phase III studies that demonstrated the efficacy of cariprazine for acute manic and mixed episodes of bipolar I disorder.


Background

  • Aim: to evaluate the efficacy, safety, and tolerability of low- and high-dose cariprazine in patients with manic or mixed episodes of bipolar I disorder.


Methods

  • A randomized, double-blind, placebo-controlled, study design was used.
  • Patients were randomly assigned to receive cariprazine 3 to 6 mg/day, cariprazine 6 to 12 mg/day, or placebo for 3 weeks.
  • The primary efficacy measure was change from baseline to week 3 in the total score on the Young Mania Rating Scale (YMRS).


Results

  • 497 patients were randomized in the study.
  • Patients in both cariprazine groups showed statistically significantly greater improvement on the YMRS (and the Clinical Global Impression-Severity scale) than patients who received placebo.
  •  Patients in both cariprazine groups also showed statistically significantly greater improvement on each of the 11 YMRS items than patients who received placebo.
  • The only common treatment-emergent adverse event (occurring in 5% or more of patients on cariprazine 3 to 6 mg/day and at least twice as often as on placebo) was akathisia:

 

Placebo

Cariprazine

3 to 6 mg/day

Cariprazine

6 to 12 mg/day

Akathisia

4%

17%

22%



Conclusions

  • Both low- and high-dose cariprazine were efficacious in the treatment of manic or mixed episodes of bipolar I disorder.


Clinical Commentary

  • The Prescribing Information for cariprazine notes that the FDA approved dose of cariprazine for bipolar mania is 3 to 6 mg/day (with a starting dose of 1.5 mg/day).
  • It also notes that doses above 6 mg/day don’t offer significant benefit but increase the risk of adverse effects.

 

Can we use subtypes of depression to predict antidepressant response?

 Arnow et al. Depression Subtypes in Predicting Antidepressant Response: A Report From the iSPOT-D Trial. Am J Psychiatry. 2015 Aug 1;172(8):743-50. PubMed PMID: 25815419.


Why is this study important?

  • At present there are no good predictors of antidepressant response. Clinicians use the trial and error method to come up with the right treatment.


Background

The aims of this study were:

1) to describe the proportions of individuals who met criteria for melancholic, atypical, and anxious depressive subtypes, as well as subtype combinations, in a large sample of depressed outpatients, and

2) to compare subtype profiles on remission and change in depressive symptoms after treatment with one of three antidepressant medications.


Methods

  • This study included patients with major depressive disorder who were 18 to 65 years of age (N=1,008)
  • Patients were randomly assigned to eight weeks of treatment with escitalopram, sertraline, or extended-release venlafaxine.
  • Participants were classified by subtype. Those who met criteria for no subtype or multiple subtypes were classified separately, resulting in eight mutually exclusive groups.
  • Remission from depression was defined as a score ≤5 on the 16-item Quick Inventory of Depressive Symptomatology-Self-Report.


Results

  • Thirty-nine percent of participants exhibited a pure-form subtype, 36% met criteria for more than one subtype, and 25% did not meet criteria for any subtype.
  • There was no difference in the remission rates between different subtypes


Conclusions

  • There was substantial overlap of the three depressive subtypes.
  • Patients in all subtype groups responded similarly to the three antidepressants.
  • These findings are consistent with those of the STAR*D study that suggested that subtypes of depression may be of little value in choosing the antidepressant.


Clinical Commentary

  • In the past, it was important to identify atypical depression since it responded better to MAO inhibitors than to tricyclic antidepressants. However, SSRIs are equally efficacious for typical and atypical depression.
  • There are separate questions of whether or not the subtypes of major depressive disorder (anxious, melancholic, atypical) may be helpful in identifying patients who may need adjunctive treatment for anxiety (anxious subtype?), may benefit more from medication than psychotherapy alone (melancholic subtype?), or may be more likely to have bipolar depression (atypical subtype?).


Should we insist that our patients get ultrabrief pulse ECT?

Tor et al. A systematic review and meta-analysis of brief versus ultrabrief right unilateral electroconvulsive therapy for depression. J Clin Psychiatry. 2015 Jul 21. [Epub ahead of print]

PubMed PMID: 26213985.


Why is this study important?

  • Electroconvulsive therapy (ECT) remains an important treatment modality that we should refer our patients for when clinically appropriate.
  • However, one of the important reasons why many patients are reluctant to get ECT is cognitive impairment.
  • If there is a type of ECT treatment that has lesser risk of cognitive adverse effects, this would make the treatment more palatable to patients.
  • Right unilateral (RUL) electrode placement has less cognitive adverse effects than bilateral ECT. Also, brief pulse square waveform stimuli lead to less cognitive adverse effects than sine wave stimuli. Moving from sine wave to brief pulse waveform was an important advance in ECT.
  • More recently, ultra brief pulse (UBP) stimulation has been developed where each pulse is only about 0.3 seconds versus 0.5 to 1.3 milliseconds for brief pulse stimuli.


Background

  • Ultrabrief pulse (UBP) right unilateral (RUL) ECT is being increasingly used for the treatment of depressive disorder.
  • Is it true that UBP-RUL ECT has lesser cognitive side effects?
  • Is it as efficacious as standard brief pulse (BP) RUL ECT?
  • Since several smaller studies have been done and the results have been conflicting, this paper did a systematic review and meta-analysis of the studies to answer these questions.


Methods

  • Multiple databases were systematically searched for relevant studies comparing UBP-RUL ECT to BP-RUL ECT for depressive disorders.
  • Papers included were those in English, which can be source of bias since clinical trials published in other languages (e.g., Japanese) are just as relevant as those published in English
  • The papers included were published by June 2013. Knowing this lets us know that we must check to see if any study has been published since then.
  • Six studies met the inclusion criteria; 689 patients were evaluated in these clinical trials.


Results

  • The mean number of ECT sessions given was greater for UBP-RUL ECT (9.6 sessions) than for BP-ECT (8.7)
  • BP-RUL ECT was slightly more efficacious in treating depression than UBP-RUL ECT. The effect size was 0.25 (small), for those who understand that concept. But, clinicians can understand how much of a difference there was by looking at the differences in response and remission rates (below).
  • When only the four studies that were randomized and double blind (i.e., higher quality) were included, there was no statistically significant difference in efficacy.
  • At the end of ECT treatment, response rates (50% or greater reduction in severity of depression) were 58% for BP-RUL ECT and 55% for UBP-RUL ECT.
  • Rates of remission (minimal remaining symptoms of depression) were 45% for BP-RUL ECT and 34% for UBP-RUL ECT.
  • However, UBP-RUL ECT resulted in less cognitive adverse effects. The largest advantages were for anterograde learning and recall, but there was an advantage in other cognitive domains that were evaluated as well, i.e., global cognition, retrograde memory.
  • The effect size was the advantage of lesser cognitive adverse effects was moderate for most measures (0.36 to 0.56).


Conclusions

  • BP-RUL ECT was slightly more efficacious than UBP-RUL-ECT in treating depression and required fewer treatment sessions, but led to greater cognitive side effects.


Clinical Commentary

  • As referring clinicians, we should be aware of these differences between BP-RUL ECT and UBP-RUL ECT.
  • Important! Not all institutions have UBP ECT and will probably not tell you or your patient that this is even an option.
  • If I put myself in the patient’s shoes, unless it was an emergency situation, I think I would insist on going to a place where UBP-ECT was available. So, I am going to insist on that for my patients as well.


Did you find these research summaries clear and easy to understand? Did you find them clinically useful? Your feedback is very important! Please send me your thoughts at [email protected].


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