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Issue 50, Jun 2016
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Another medication for adjunctive use in major depressive disorder?

Durgam S, Earley W, Guo H, Li D, Németh G, Laszlovszky I, Fava M, Montgomery SA. Efficacy and safety of adjunctive cariprazine in inadequate responders to antidepressants: a randomized, double-blind, placebo-controlled study in adult patients with major depressive disorder. J Clin Psychiatry. 2016 Mar;77(3):371-8. PubMed PMID: 27046309.

Cariprazine is a recently introduced second-generation (“atypical”) antipsychotic that is approved by the FDA for the treatment of schizophrenia and for the acute treatment of manic or mixed episodes associated with bipolar I disorder.

It is not currently approved as an adjunct to antidepressants in persons with major depressive disorder whose illness has not responded adequately to an antidepressant. However, other second-generation antipsychotics are commonly used for this indication. Thus, this study provides data on a different potential use of cariprazine.


This study is part of a development program by the manufacturer to seek FDA-approval for the use of cariprazine as an adjunctive treatment for major depressive disorder with an inadequate response to standard antidepressant therapy.


This was a randomized, double-blind, placebo-controlled, clinical trial. 

Adults with major depressive disorder who had had an inadequate response to an antidepressant were included.

Patients were randomized to 8-weeks of adjunctive treatment (i.e., along with the antidepressant) with cariprazine flexible dose from 1 to 2 mg/day (n = 274), cariprazine 2 to 4.5 mg/day (n = 276), or placebo (n = 269).

The primary outcome measure was reduction in severity of depression as measured by the total score on the Montgomery-Asberg Depression Rating Scale (MADRS).


After 8 weeks of treatment, patients who received adjunctive cariprazine 2 to 4.5 mg/day had a statistically significantly greater reduction in the severity of depression than patients who received adjunctive placebo.

What about the lower dose, 1 to 2 mg/day? After 8 weeks of treatment, patients who received adjunctive cariprazine 1 to 2 mg/day did not have statistically significantly greater improvement than patients on placebo (although there was a difference at some earlier visits).

OK, but how many patients improved significantly? “Response” in major depressive disorder is defined as a 50% or greater reduction in the severity of depression. The percentage of “responders” was 38% on placebo, 48% on cariprazine 1 to 2 mg/day, and 49% on cariprazine 2 to 4.5 mg/day.  

Even though cariprazine 1 to 2 mg/day was not statistically significantly more efficacious than placebo based on the primary outcome measure, we should not write it off as not efficacious because this lower dose was efficacious when looked at in other ways, i.e, percentage of responders, improvement on the Clinical Global Impression scale.

How early did the improvement start? There were statistically significant differences between cariprazine 2 to 4.5 mg/day and placebo starting after 2 weeks of treatment.

Treatment-emergent adverse events that occurred in 5% or more of patients on cariprazine and at least twice as often as on placebo were as follows. (These are the criteria I recommend for deciding which ones are “common adverse effects.”)

Adverse Effect


Cariprazine 1 to 2 mg/day

Cariprazine 2 to 4.5 mg/day

































Increased appetite




The paper notes that “Mean changes in metabolic parameters, vital signs, and ECG parameters were generally similar between groups.” However, as clinicians we are more interested in knowing how many patients had clinically meaningful changes in these variables.

The percentages of patients with 7% or greater increase in body weight from baseline were: placebo 2%, cariprazine 1 to 2 mg/day 2%, cariprazine 2 to 4.5 mg/day 3%. So, very few patients gained a significant amount of weight in this short-term study.

There was no difference in the percentage of patients who had orthostatic hypotension.

No patient had a QTc of > 500 msec.

Mean increases in prolactin: placebo 0.7 ng/mL, cariprazine 1 to 2 mg/day 3.8 ng/mL, cariprazine 2 to 4.5 mg/day 4.1 ng/mL. The percentages of patients with clinically meaningful increases in prolactin were not described. But the mean changes show a slightly greater mean increase in prolactin in patients on cariprazine.


Cariprazine 2 to 4.5 mg/day added to an antidepressant was efficacious in patients with major depressive disorder who had had an inadequate response to standard antidepressants.

Clinical Commentary

For a medication to be considered clinically useful, it is generally agreed that the drug must be efficacious in at least 10% more patients than placebo. Cariprazine does meet this minimum criterion. Note that this drug-placebo difference was about 10% for aripiprazole as well. Adjunctive use of second-generation antipsychotics, while now well documented and a valuable tool in our armamentarium, is efficacious in a minority of patients. Unfortunately, we don’t have any clinically useful predictors of who those patients are.

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Is varenicline (Chantix) useful and safe for persons with mental disorders?

Anthenelli et al. Neuropsychiatric safety and efficacy of varenicline, bupropion, and nicotine patch in smokers with and without psychiatric disorders (EAGLES): a double-blind, randomised, placebo-controlled clinical trial. Lancet. 2016 Apr 22. pii: S0140-6736(16)30272-0. [Epub ahead of print] PubMed PMID: 27116918.

Smoking remains an important health problem and the proportion of smokers in much higher in persons with mental disorders.

Varenicline (ChantixÒ) and bupropion (ZybanÒ) are efficacious medications for smoking cessation. However, case reports and post-marketing data suggested that varenicline and bupropion might be associated with neuropsychiatric adverse events. Hence, there has been a reluctance to prescribe it for persons with mental health problems.

The FDA issued a post-marketing requirement to the makers of varenicline and bupropion to do a randomized controlled trial to assess the risk of serious neuropsychiatric adverse events. The result is the present study that was designed in consultation with the FDA.

This study provides valuable data on the safety of varenicline and bupropion in persons with and without mental disorders.

The study also provides the first definitive evidence on the relative efficacy of different smoking cessation medications in smokers with mental disorders.


This study addresses two limitations of previously available data:

1. There is limited information on both the safety and the efficacy of varenicline and bupropion in smokers with mental disorders.

2. Are varenicline and bupropion more efficacious than the nicotine patch? There is little data available that directly compares these treatments.

Therefore, this study evaluated the neuropsychiatric safety and the efficacy of varenicline and bupropion compared to the nicotine patch and to placebo in smokers either with or without mental disorders.


This was a randomized, double-blind, clinical trial with both a placebo control and a nicotine patch control. It was conducted in 16 countries.

Smokers with or without mental disorders who were motivated to quit were recruited. The subjects smoked, on an average, ten or more cigarettes per day.

Subjects in the group with mental disorders suffered from various disorders including mood disorders, anxiety disorders, psychotic disorders, and borderline personality disorder. However, the mental disorder had to be stable. Also, persons who had another substance use disorder in the preceding 12 months were excluded.

The treatment groups were:

1. Varenicline 1 mg twice a day

2. Bupropion 150 mg twice a day

3. Nicotine patch 21 mg per day with taper

4. Placebo

Brief smoking-cessation counseling was also provided at each visit.

Treatment was provided for 12 weeks and a follow-up was done after another 12 weeks.

The primary outcome measure for safety was the incidence of a composite measure of moderate and severe neuropsychiatric adverse events. Thus, instead of the primary outcome measure being any one adverse event, several moderate and severe neuropsychiatric adverse events were combined into one primary outcome measure. Why? One advantage of using a composite measure is that allows for just one statistical test for the main analysis. Also, any one adverse event may be rare, but combining them increases the total number of adverse events, giving greater statistical power.

The primary outcome measure for efficacy was continuous abstinence for weeks 9 to 12. The abstinence was confirmed by testing for exhaled carbon monoxide.


8144 subjects were randomized, including 4116 to the group with mental disorders and 4028 to the group without mental disorders. This was a huge study!

So, what were the main findings? Moderate or severe neuropsychiatric adverse events were experienced as follows:



Without mental disorders

With mental disorders







Nicotine patch







Within each category—with or without mental disorder—these proportions for the different treatment groups were not statistically significantly different. That is, while there were more neuropsychiatric adverse events in patients with mental disorders, these were not related to any one treatment.

Did the treatments work? All three active treatments were more efficacious than placebo: varenicline (odds ratio 3.6), bupropion (odds ratio 2.1), and nicotine patch (odds ratio 2.2)

Was one treatment better than another? Persons who received varenicline were more likely to be abstinent from smoking compared to bupropion (odds ratio 1.8) and compared to the nicotine patch (odds ratio 1.7).

Was the efficacy different in persons with or without mental disorders? No.


The study did not find an increase in neuropsychiatric adverse events in persons treated with varenicline or bupropion when compared to those treated with a nicotine patch or placebo.

All three treatments were more efficacious than placebo.

Varenicline was more efficacious than bupropion and the nicotine patch.

Clinical Commentary

An accompanying commentary (Zawertailo, 2016) noted that while neuropsychiatric adverse events were more common in patients with mental disorders, they seemed to be related to smoking cessation itself and not to any particular medication used.

Two caveats:

1. The subjects in this study were psychiatrically stable. Safety of varenicline and bupropion in persons with more actively mental disorders should not be assumed.

2. As the authors acknowledge, this study cannot completely rule out the possibility that varenicline or bupropion are associated with neuropsychiatric adverse events in persons with mental disorders. It can only show that if the there is such an association, it is uncommon. Thus, while the results of this study are very welcome, we should continue to be cautious and monitor patients whom we treat with these medications, especially those with other mental disorders.

It should be noted that for now, the boxed (“black box”) warnings for both varenicline and bupropion remain in place.

Given the serious consequences of smoking, the high prevalence of smoking in persons with mental disorders, and how difficult it is to quit smoking, it would be very unfortunate if smokers with mental disorders were deprived of efficacious smoking cessation medications.

Patients with mental disorders who are quitting smoking should be told that significant changes in their mood and mental functioning might occur during the process of quitting, though probably not due to any particular medication.

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Does citalopram work for neuropsychiatric symptoms in Alzheimer’s dementia?

Leonpacher et al.; CitAD Research Group. Effects of Citalopram on Neuropsychiatric Symptoms in Alzheimer's Dementia: Evidence From the CitAD Study. Am J Psychiatry. 2016 May 1;173(5):473-80. PubMed PMID: 27032628.

Neuropsychiatric symptoms are common in Alzheimer’s dementia and are associated with considerable morbidity. Their management is, therefore, very important.

We have previously discussed data from the Citalopram for Agitation in Alzheimer's Disease (CitAD) study about the efficacy of citalopram for agitation in persons with Alzheimer’s dementia. See

What about the efficacy of citalopram for other neuropsychiatric symptoms? The paper being discussed here provides data from the same CitAD study about the efficacy of citalopram for these other symptoms.


This paper describes a planned secondary analysis of the CitAD study. The primary analysis was about the efficacy of citalopram for agitation in these patients. In this paper, the efficacy of citalopram for other neuropsychiatric symptoms is evaluated.


Patients with probable Alzheimer’s disease and agitation (n=186) were enrolled in the trial.

Patients were randomized to 9 weeks of treatment with either citalopram or placebo.

Citalopram was started at 10 mg/day and increased up to 30 mg/day if needed and tolerated.

The efficacy of citalopram for the 12 neuropsychiatric symptom domains assessed by the Neuropsychiatric Inventory (NPI) was assessed. The Neuropsychiatric Inventory is completed by the patient’s caregiver.

NPI scores after 9 weeks of treatment were compared between patients with Alzheimer’s disease who received citalopram 30 mg/day or placebo.


The symptoms were analyzed in two ways—based on presence/absence and based on severity.

Based on just presence or absence, after 9 weeks of treatment, patients treated with citalopram were statistically significantly less likely to be reported as showing delusions, anxiety, or irritability/lability (odds ratio=0.4 for each).

Based on severity of symptoms, patients treated with citalopram had lower severity of hallucinations compared to placebo. On the other hand, patients treated with citalopram had greater severity of sleep/nighttime behavior disorders.


Nine weeks of treatment with citalopram up to 30 mg/day was efficacious for agitation/aggression, irritability, anxiety, delusions, and hallucinations in patients with Alzheimer’s disease. However, there was an increase in the severity of sleep/nighttime behavior disorders.

Clinical Commentary

Given the concerns about increased mortality associated with use of antipsychotics in elderly patients with dementia-related psychosis, we should probably use citalopram as an alternative more often.

However, after this study was underway, the FDA issued a warning about risk of QT prolongation with citalopram. In elderly patients, we should not use citalopram at a dose greater than 20 mg/day.

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Do omega-3 fatty acids help to treat depression?

Hallahan et al. Efficacy of omega-3 highly unsaturated fatty acids in the treatment of depression. Br J Psychiatry. 2016 Apr 21. pii: bjp.bp.114.160242. [Epub ahead  of print] PubMed PMID: 27103682.

There is frequently a need for adjunctive treatment of major depressive disorder.

Patients often express an interest in use of supplements to treat mental disorders. Among these, omega-3 fatty acids have received a lot of attention. However, we need to have a scientifically rigorous answer as to whether they work for clinical depression. If they do work, they are a very attractive option for adding onto antidepressants.


The results of clinical trials evaluating the efficacy of omega-3 highly unsaturated fatty acids (HUFAs) for major depressive disorder have been inconsistent.


A systematic literature search was done to identify double-blind randomized controlled trials (RCTs) of omega-3 HUFAs. The search strategy was thorough and included multiple databases, references of papers,, and consultations with experts on the topic.

Randomized, controlled trials of either monotherapy or adjunctive therapy with omega-3 HUFAs in persons with unipolar depression, bipolar depression, or depressive symptoms were included in the meta-analysis.

A meta-analysis of 35 RCTs was done. These trials including 6665 participants receiving omega-3 HUFAs and 4373 participants receiving placebo.


There are several omega-3 HUFAs and different formulations contain more of one or the other type. Among subjects diagnosed with clinical depression, formulations of omega-3 HUFAs that contained more than 50% eicosapentaenoic acid (EPA) were more efficacious than placebo.

In those diagnosed with clinical depression, the effect size for these formulations with more than 50% EPA was 0.6, which indicates a moderate effect size.

There was no difference between formulations that contained more than 50% EPA and those that contained more than 80% EPA.

On the other hand, formulations of omega-3 HUFAs that contained more than 50% of docosahexanoic acid (DHA) were not more efficacious than placebo.

EPA was efficacious for both unipolar and bipolar depression.

While EPA was efficacious both as monotherapy and as adjunctive therapy, it seems that it is more efficacious as adjunctive therapy. The effect size was lower for monotherapy (0.3) than for adjunctive use (0.6).

Among subjects who were “depressed” but not diagnosed with clinical depression, even formulations that had mostly eicosapentaenoic acid (EPA) were not efficacious.


Future research should focus on those with diagnosed or clinically significant depression and omega-3 HUFA formulations containing more than 50% eicosapentaenoic acid (EPA) should be used.

Clinical Commentary

In my clinical practice, I am now routinely recommending omega-3 fatty acids (containing more than 50% EPA) in addition to other medications for patients with depressive disorders and bipolar disorders.

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Will patients escalate to high doses of benzodiazepines?

Alessi-Severini S, Bolton JM, Enns MW, Dahl ME, Chateau D, Collins DM, Sareen J. Sustained Use of Benzodiazepines and Escalation to High Doses in a Canadian Population. Psychiatr Serv. 2016 May 2:appips201500380. [Epub ahead of print] PubMed PMID: 27133727.

Benzodiazepines are very effective for treatment of generalized anxiety or panic disorder.

However, clinicians are rightly concerned about the risk of dependence, tolerance, and constantly increasing doses.

On the other hand, for some patients, these fears can also inappropriately deprive patients of very helpful medication.

The media sometimes promotes an image of the person on long-term benzodiazepine therapy as an addict who will inevitably escalate to high-dose use.

So, an important clinical question is: if we prescribe a benzodiazepine for a longer period (say, 2 years or more), how likely is it that those patients will eventually increase to higher than recommended doses?


Whether longer-term use leads to escalation to high doses of benzodiazepines is not known.

This study assessed the extent of dose escalation among individuals who took a benzodiazepine (or zopiclone) for two years or more.


This was a population-based study conducted in the Canadian province of Manitoba using administrative health-related databases rather than directly assessing patients.

The authors defined sustained use as largely continuous use for at least two years. Based on this definition, 12,598 patients with sustained use were identified in the database.

Doses of the different benzodiazepines were converted into their equivalent dose of diazepam. These are called diazepam milligram equivalents (DMEs).

Dose escalation was defined as an increase in dose above the recommended dose to more than 40 DMEs for persons less than 65 years old or more than 20 DMEs for persons more than 65 years old.


Of the persons who were prescribed a benzodiazepine/zopiclone, only 4% were sustained users of benzodiazepines (i.e., took it for 2 years or more).

How many persons started with a usual dose but escalated to a high dose? This was 0.3% of all persons prescribed a benzodiazepine/zopiclone or less than 8% of the patients with sustained use of a benzodiazepine.

Rates of potential "doctor shopping" and "pharmacy hopping" were low, but were higher among younger adults, compared with older adults.


Only a small proportion of sustained users of benzodiazepines escalated to higher than recommended doses.

Clinical Commentary

This study suggests that the risk of dose escalation after sustained benzodiazepine use is less than is commonly thought.

Patients for whom longer-term benzodiazepine use is clinically appropriate and who are being appropriately monitored should not automatically be deprived of efficacious treatment simply due to a non-specific concern about potential dose escalation.

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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.

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]

To contact GME, email us at [email protected]

GME does not provide medical advice. The website and articles are intended for informational purposes only. They are not a substitute for professional medical advice, diagnosis or treatment. Never ignore professional medical advice in seeking treatment because of something you have read on the GME Website. If you think you may have a medical emergency, immediately call your doctor or dial 911.

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