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Tardive Dyskinesia: What Are We Missing?

Earn 1.5 CME/CE credits at this complimentary lunch and interactive CME symposium at the US Psych Congress meeting in San Antonio, TX. 

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FRIDAY, OCTOBER 21, 2016
Henry B. Gonzalez Convention Center
Stars at Night B4
900 East Market Street
San Antonio , TX

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Issue 51, Jul 2016
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What is the best way to quickly screen for possible borderline personality disorder?

Zimmerman et al. A Clinically-Useful Screen for Borderline Personality Disorder in Psychiatric Outpatients. Poster presented at the annual meeting of the American Psychiatric Association, May 2016, Atlanta, Georgia.

Why is this study important?

The under-recognition of borderline personality disorder has been identified as a significant clinical problem.

A brief screening tool to screen for borderline personality disorder would be very useful in clinical practice. If the person screened positive, a more detailed assessment would be done.

Background

A major barrier to identifying borderline personality disorder in clinical practice is the fact that these persons very commonly have comorbid anxiety, mood, or substance use disorders.

Methods

3674 subjects being evaluated at an outpatient psychiatry clinic were evaluated at initial intake.

The mean age of these patients was 39 years and 60% of them were female.

Semi-structured diagnostic interviews were used—the Structured Clinical Interview for the DSM-IV (SCID) and the borderline personality disorder section of the Structured Interview for DSM-IV Personality Disorders (SIDP-IV).

Sensitivity, specificity, positive predictive value, and negative predictive value were determined for each of the nine DSM-IV diagnostic criteria for borderline personality disorder. However, since the study aimed to identify the best approach to screening, the most important characteristic to look at is sensitivity.

Results

The prevalence of borderline personality disorder in these patients was 11%.

As hypothesized by the investigators, the diagnostic criterion that had the highest sensitivity (93%) was Affective Instability.

The DSM-IV-TR criterion describes this as “affective instability due to a marked reactivity of mood (e.g., intense episodic dysphoria, irritability, or anxiety usually lasting a few hours and only rarely more than a few days).”

The Affective Instability criterion was present in 93% of subjects with borderline personality disorder (sensitivity). That is, only 7% of persons with borderline personality disorder did not meet the Affective Instability criterion.

If Affective Instability was absent, 99% of those persons did not have borderline personality disorder (negative predictive value).

However, only 38% of persons in whom the Affective Instability criterion was present met DSM-IV-TR criteria for borderline personality disorder (positive predictive value). This could mean that there are causes of Affective Instability other than borderline personality disorder or that many persons with Affective Instability had subthreshold symptoms of borderline personality disorder. 

Conclusions

Which characteristic should we use to judge how useful it is to evaluate the use of the Affective Instability criterion? This depends on what we are aiming to do.  The Affective Instability criterion is not intended to diagnose borderline personality disorder; it is intended as a screening tool to identify everyone (or almost everyone) who might have the disorder. Therefore, as for all screening tools, the most important characteristics are:

In what percentage of persons who really have the disorder is the screening criterion present (Sensitivity)?

In persons in whom the screening criterion is absent, in what percentage is the disorder absent (Negative predictive value).

The combination of high sensitivity (93%) and high negative predictive value (99%) suggest that if all persons undergoing a mental health evaluation were evaluated for the presence or absence of Affective Instability, very few persons with borderline personality disorder would be missed.

Clinical Commentary

A major strength of this study, as for all the work coming from this group, is that the data is from all patients seen in a busy outpatient clinical practice. That is, these patients from the Rhode Island Hospital Methods to Improve Diagnostic Assessment and Services (MIDAS) project are “real world” patients.

We must screen for common, important disorders in all patients just like other clinicians do a review of systems. Borderline personality disorder is certainly one of the disorders that can have very serious adverse effects on the person suffering from it. So, let’s resolve to screen all adult patients for borderline personality disorder. This study provides us guidance about which criterion to use for the purposes of quick screening. If Affective Instability is present, we should set aside time to assess the person for all the other criteria as well.

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What medication or combinations do adults with ADHD take?

Zhou Z et al. Medication Use among Commercially-insured Adults with Attention-Deficit/Hyperactivity Disorder in the US. Poster presented at the annual meeting of the American Psychiatric Association, May 2016, Atlanta, Georgia.

Why is this study important?

Do you prescribe monotherapy to most adult patients with ADHD? Do you almost always use long-acting stimulants? When you use combinations of more than one medication, which ones do you use the most? Answer these questions and then compare your practices to those of other clinicians throughout the US.

Knowing what treatments clinicians are using in “real world” patients is helpful for understanding what issues they are facing with their patients.

Background

In contrast to a decade or two ago, Attention-Deficit Hyperactivity Disorder (ADHD) is now recognized as a lifespan disorder, rather than one which persons suffering from it “outgrow.”

However, little is known about real-world pharmacological treatment among adults with ADHD.

This study, looked at the what medications are prescribed to adults with ADHD in the US.

The study was sponsored by Shire Development, LLC.

Methods

A large database of persons who had a commercial medical insurance in the US was used.

Adults (18 years of age or older in 2013) who had a diagnosis of ADHD on at least 2 consecutive visits and who received at least one ADHD medication were included in the analysis

Combination therapy was defined as use of two or more ADHD medications together for 30 days or more.

Duration of effect of medication is a key factor in choosing ADHD medications and was used to classify the patterns of medication use.

Results

The study included about 206,000 adults with a diagnosis of ADHD.

The mean age of the patients was 33 years.

Of these patients, 52% were female. That’s interesting, isn’t it? In children, boys are diagnosed much more often than girls.

There were six mutually exclusive treatment groups. Combining generic and branded medications, three treatment patterns were most common:

1. Monotherapy with a long-acting medication—57% of the patients.

2.  Monotherapy with a short-acting medication—31%

3. Combination of a long-acting and a short-acting medication—10%


Combining generic and branded medications, the other three treatment patterns were quite uncommon:

4. Combination of two long-acting medications—1%

5. Combination of two short-acting medications—0.5%

6. Combination of more than two medications—0.5%


The most common prescriptions for long-acting medications used as monotherapy were:

1. Mixed amphetamine salts extended-release (39%)

2. Lisdexamphetamine (32%)

3. Methylphenidate long-acting preparations (20%).


The most common prescriptions for short-acting medications used as monotherapy were:

1. Mixed amphetamine salts—82%

2. Methylphenidate—15%


The most common prescriptions for a long-acting plus a short-acting preparation were:

1. Mixed amphetamine salts extended-release (generic) plus mixed amphetamine salts (generic)—39%

2. Lisdexamfetamine plus mixed amphetamine salts (generic)—17%

3. Methylphenidate long-acting preparation (generic) plus methylphenidate (generic)—13%


The most commonly used combinations of prescriptions for two long-acting medications were:

1. Mixed amphetamine salts (branded) plus mixed amphetamine salts (generic)—14%

2. Lisdexamfetamine plus mixed amphetamine salts (generic)—11%

3. Lisdexamfetamine plus guanfacine extended-release—11%

 

The most frequently used combinations of two short-acting preparations were:

1. Mixed amphetamine salts (generic) plus clonidine immediate-release—34%

2. Mixed amphetamine salts (generic) plus methylphenidate generic—18%

3. Mixed amphetamine salts (branded) plus mixed amphetamine salts  (generic)—11%

Conclusions

The majority (57%) of adults with ADHD in a commercially-insured US population were treated with monotherapy with a long-acting stimulant. Others (31%) received monotherapy with a short-acting medication.

However, 12% of patients received a prescription for more than one medication for ADHD during the same 30-day period.

Clinical Commentary

Psychopharmacological treatment of ADHD in adults is both an art and a science. Duration of effect is probably the most important factor to consider. However, there is more than one way to achieve all-day coverage, optimized for the time of the day when the person needs more medication.

This study showed that a high percentage of adults with ADHD are treated with monotherapy, but it also showed that there are many other combinations that are used.

Clinicians treating ADHD should become skillful in using various preparations and combinations of preparations.

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Safety and efficacy of cariprazine in FDA-approved dose ranges

Earley et al. Safety and Efficacy of Cariprazine in FDA-Approved Dose Ranges for Schizophrenia and Bipolar I Disorder: A Pooled Post Hoc Analysis. Poster presented at the annual meeting of the American Psychiatric Association, May 2016, Atlanta, Georgia.

Why is this study important?

For any medication, it is hard for clinicians to read even the summaries of the many studies done. Pooled analyses are one way of putting data from many studies together.

However, in the case of this study, there is another reason why it is clinically important. Several studies in both schizophrenia and bipolar disorder had been done that used a wide range of doses. However, the FDA only approved a narrower range of doses. Thus, it is important to know both the efficacy and the adverse effects when cariprazine is used at the FDA-approved doses.

Background

Cariprazine is a dopamine D3/D2 receptor partial agonist that was approved by the FDA in late 2015 for the treatment of schizophrenia and for manic or mixed episodes associated with bipolar I disorder.

Several of the studies of cariprazine used flexible doses, i.e., the dose could be changed during the study. This is a pooled post-hoc analysis to evaluate the safety and tolerability of cariprazine when the most frequently used dose (the modal dose) was within the FDA-approved dose range FDA-approved dose range—schizophrenia 1.5 to 6 mg/day, bipolar mania 3 to 6 mg/day.

Methods

Data were pooled for each indication separately. For schizophrenia, four 6-week trials were included. For bipolar disorder three 3-week trials were included.

For safety analyses, patients were grouped into groups based on the modal daily dose as outlined below.

Schizophrenia:

Placebo (n=584)

Cariprazine 1.5 to 3 mg/day (n=539)

Cariprazine 4.5 to 6 mg/day (n=575).

Bipolar disorder:

Placebo (n=442)

Cariprazine 3 to 6 mg/day (n=263).

Results

Cariprazine was statistically significantly more efficacious than placebo in 3 of the 4 clinical trials in patients with schizophrenia.

Cariprazine was statistically significantly more efficacious than placebo in all 3 clinical trials in patients with bipolar disorder.

The most commonly reported treatment-emergent adverse events that occurred in at least 5% of patients and at least twice as often as placebo are shown below.  


Schizophrenia studies: 

 

Placebo

Cariprazine

1.5 to 3 mg/day

Cariprazine

4.5 to 6 mg/day

Akathisia

4%

9%

13%

Extrapyramidal disorder

3%

7%

8%

Tremor

2%

4%

5%


Bipolar disorder studies: 

 

Placebo

Cariprazine

3 to 6 mg/day

Akathisia

5%

20%

Restlessness

2%

7%

Vomiting

4%

10%


In the FDA-approved dose range, no patient on cariprazine had a QTcB or QTcF interval >500 msec.

The percentages of patients whose cholesterol, triglycerides, or fasting glucose changed from normal to abnormal were similar between cariprazine and placebo.

The percentages of patients who gained 7% of more from their baseline weight (the standard definition of clinically significant weight gain) were as shown below.

Schizophrenia studies:

Placebo 5%, cariprazine 1.5 to 3 mg/day 8%, cariprazine 3 to 6 mg/day 8%.

Bipolar disorder studies:

Placebo 2%, cariprazine 3 to 6 mg/day 1%

Conclusions

Cariprazine has been shown to be efficacious in the FDA-approved dose ranges in patients with acute exacerbation of schizophrenia and bipolar mania.

The commonest adverse events associated with cariprazine were akathisia, extrapyramidal symptoms, tremor, restlessness, and vomiting.

Cariprazine was not associated with worsening of lipid profile or fasting blood glucose, or with prolongation of QTc interval.

Clinical Commentary

Cariprazine has been shown to be efficacious in FDA-approved dose ranges and its adverse effect profile is what is to be expected based on its pharmacological activity as a D3/D2 receptor partial agonist.

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New medications may soon be available for tardive dyskinesia: Valbenazine

Marder et al. KINECT 3: A Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial of Valbenazine (NBI-98854) for Tardive Dyskinesia. Poster presented at the annual meeting of the American Psychiatric Association, May 2016, Atlanta, Georgia.

Why is this study important?

Tardive dyskinesia (TD) is one of the most important adverse effects of antipsychotic treatment because it often persists and can be disfiguring and even disabling.

However, there are currently no FDA-approved treatments for TD. Available treatments either do not work well or are extremely expensive (tetrabenazine). Tetrabenazine is FDA-approved only for Huntington’s disease. Also, it has been associated with neurological and psychiatric adverse effects in persons with Huntington’s disease.

Background

Valbenazine is a drug being developed for the treatment of tardive dyskinesia that has completed phase III studies, but is not yet approved by the FDA.

It is a highly selective vesicular monoamine transporter 2 (VMAT2) inhibitor. The vesicular monoamine transporter 2 (VMAT2) is a protein in the presynaptic neuron that regulates monoamine (e.g., dopamine) uptake from the cytoplasm to the synaptic vesicle. With the dopamine thus stored away, dopamine levels in the synapse are reduced, which in turn improves the symptoms of TD. Note: the existing medication tetrabenazine is also a VMAT2 inhibitor.

This was a phase 3 study and was sponsored by the Neurocrine Biosciences, Inc, that is developing this drug.

Methods

This was a 6-week, double-blind, placebo-controlled clinical trial

Persons with moderate or severe antipsychotic-induced TD were included.  These persons had schizophrenia, schizoaffective disorder, or a mood disorder.

They were randomized to receive valbenazine 40 mg/day, valbenazine 80 mg/day, or placebo.

The primary outcome measure was the score on the Abnormal Involuntary Movement Scale (AIMS). AIMS assessment was done by central video raters who were blinded to the treatment.

Results

234 subjects were randomized.

86% of the subjects were currently receiving an antipsychotic medication (second-generation or “atypical” antipsychotic 77%; first-generation or “typical” antipsychotic 16%).

The mean AIMS score before treatment was 10.

There was a statistically significantly greater improvement in AIMS score in patients who received either valbenazine 40 mg/day or 80 mg/day compared to those who received placebo.

Better by how much? The estimated mean reduction in AIMS score with valbenazine 80 mg/day was 3.2 points and with 40 mg/day was 1.9 points versus only 0.1 points on placebo. That is a clinically meaningful difference between drug and placebo when you compare the reduction to the baseline AIMS score (mean of 10).

Another way of looking at how much of a benefit there was is Effect Size. An effect size of 0.8 is considered a large effect and for the benefit of valbenazine 80 mg/day vs. placebo, the Effect Size was 0.9.

The Clinical Global Impression showed a lower severity of TD with valbenazine than with placebo, but this difference was not statistically significant (i.e., could have occurred by chance alone). I am not too surprised by this and we can all ponder over why the systematic assessment using the AIMS showed a statistically significant difference while the Clinical Global Impression did not.

What were the adverse effects? There were surprisingly few. Adverse effects that occurred in either of the valbenazine groups at least twice as often as on placebo were:

Akathisia: placebo 1%, valbenazine 40 mg/day 4%, valbenazine 80 mg/day 3%

Arthralgia: placebo 1%, valbenazine 40 mg/day 1%, valbenazine 80 mg/day 4%

Dry mouth: placebo 1%, valbenazine 40 mg/day 6%, valbenazine 80 mg/day 0%

Vomiting: placebo 0%, valbenazine 40 mg/day 0%, valbenazine 80 mg/day 4%

Dyskinesia: placebo 0%, valbenazine 40 mg/day 0%, valbenazine 80 mg/day 4%

Multiple rating scales (PANSS, YMRS, MADRS, CDSS, C-SSRS) were used to assess psychiatric status and it remained stable during the study.

Conclusions

Valbenazine was associated with a significant improvement in TD.

It had very few adverse effects, even when taken with a wide range of concomitant medications, including antipsychotic medications.

It did not appear to worsen psychiatric symptoms, or to lead to depression or suicidality.

Clinical Commentary

It has been very frustrating to clinicians and to patients that we have not had any effective treatments for TD that we could use in clinical practice. Tetrabenazine is very expensive and health insurance doesn’t approve it for TD. Also, tetrabenazine was associated with poor tolerability and with neurological/psychiatric adverse events.

Both the efficacy and the tolerability of valbenazine in such a short-term study are encouraging.

I would definitely like to see longer-term data to see if the TD continues to improve even further and to make sure that the improvement lasts.

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New medications may soon be available for tardive dyskinesia: Deutetrabenazine

Anderson et al. A Randomized, Double-Blind, Placebo-Controlled Trial of Deutetrabenazine for the Treatment of Tardive Dyskinesia (ARM-TD). Poster presented at the annual meeting of the American Psychiatric Association, May 2016, Atlanta, Georgia.

Why is this study important?

For the same reasons that were mentioned for the study of valbenazine discussed above:

Tardive dyskinesia (TD) is one of the most important adverse effects of antipsychotic treatment because it often persists and can be disfiguring and even disabling.

However, there are currently no FDA-approved treatments for TD. Available treatments either do not work well or are extremely expensive (tetrabenazine).  Tetrabenazine is FDA-approved only for Huntington’s disease. Also, it has been associated with neurological and psychiatric adverse effects in persons with Huntington’s disease.

Background

Deutetrabenazine is a new drug in development. It is a selective VMAT2 inhibitor that has been shown to be efficacious in reducing chorea in persons with Huntington’s disease.

Deuterium is a naturally occurring form of hydrogen. Incorporation of deuterium in deutetrabenazine changes the drug’s pharmacokinetic profile and reportedly leads to more-uniform systemic exposure.

This study aimed to evaluate the efficacy, safety, and tolerability of deutetrabenazine as a treatment for TD.

The study was funded by Teva Pharmaceutical Industries, Ltd, that is developing deutetrabenazine as a potential treatment for TD.

Methods

This was a 12-week, randomized, double-blind, placebo-controlled study.

Adults with moderate or severe TD were included.

The subjects had been treated with a dopamine receptor antagonist for at least 3 months (1 month for persons 60 years or older).

Abnormal Involuntary Movements Scale (AIMS) assessment was done by a blinded central rater.

The Abnormal Involuntary Movements Scale (AIMS) score was 6 or greater.

The psychiatric disorder and medication were stable prior to entering the study.

Deutetrabenazine was titrated to a tolerated dose that adequately controlled abnormal movements over 6 weeks. The drug was then continued at that dose for another 6 weeks.

Results

117 subjects were randomized. The mean age was 55 years; 52% were females.

Mean duration of TD was 75 months but with a lot of variability. That is, many patients had had the TD for years.

The mean AIMS score was 10.

Patients who received deutetrabenazine showed a greater reduction in AIMS score after 12 weeks of treatment (the primary outcome measure)—an estimated mean reduction of 3 points vs. 1.6 points on placebo.

On the Clinical Global Impression scale, 48% on drug were considered much improved or very much improved versus 40% on placebo. Thus, only 8% more patients who received deutetrabenazine were considered much improved or very much improved. In persons whose baseline AIMS score was 6 or more (i.e., who had more severe TD), this drug-placebo difference was 17%, which would be considered clinically meaningful. However, these differences were not clinically significant, i.e., could have occurred simply be due to chance alone. Thus, systematic, centralized assessment using the AIMS showed a statistically significant difference while the Clinical Global Impression did not.

Treatment-emergent adverse events that occurred at least twice as often on drug as on placebo were:

Insomnia (7% vs. 2%)

Akathisia (5% vs. 0%). However, surprisingly, on systematic examination using the Barnes Akathisia Rating Scale, there was no difference between drug and placebo.

Just for your amusement and to illustrate the problem of assessing and reporting adverse events in clinical trials, treatment-emergent adverse events that occurred at least twice as often on placebo as on drug were:

Dry mouth (10% vs. 3%)

Upper respiratory tract infection (7% vs. 3%)

Rash (2% vs. 5%)

Conclusions

After 12 weeks of treatment, deutetrabenazine was efficacious for the treatment of antipsychotic-induced TD.

The rate of discontinuation of treatment was low and no depression or suicidal ideation were reported. Both of these have been reported with tetrabenazine in persons with Huntington’s disease.

Clinical Commentary

My comments are the same as those for the study of valbenazine for TD that is discussed above:

It has been very frustrating to clinicians and to patients that we have not had any effective treatments for TD that we could use in clinical practice. Tetrabenazine is very expensive and health insurance doesn’t approve it for TD. Also, tetrabenazine was associated with poor tolerability and with neurological/psychiatric adverse events.

Both the efficacy and the tolerability of deutetrabenazine in such a short-term study are encouraging.

I would definitely like to see longer-term data to see if the TD continues to improve even further and to make sure that the improvement lasts.

What is the regulatory status of deutetrabenazine? In May 2016, Teva pharmaceuticals received a Complete Response Letter from the U.S. Food and Drug Administration (FDA) regarding the New Drug Application for deutetrabenazine for the treatment of chorea associated Huntington disease. The FDA has asked Teva to examine blood levels of certain metabolites, but no new clinical trials have been requested. Hopefully Teva will address the FDA concerns and  deutetrabenazine will soon be approved by the FDA for the treatment of Huntington’s chorea. A separate New Drug Application for deutetrabenazine for the treatment of tardive dyskinesia is expected to be submitted after that.

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Rajnish Mago, MD
Professor of Psychiatry, Thomas Jefferson University

GME Research Review is a monthly newsletter edited by Rajnish Mago, MD, who is 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.

 

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Irritable Bowel Syndrome: What's New for Rome IV

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SUNDAY, MAY 22, 2016
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Third Annual Mood Disorders Summit

Third Annual Mood Disorders Summit

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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.


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