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Issue 57, Jan 2017
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How does antipsychotic-induced increased prolactin affect our patients?

Rubio-Abadal et al; PROLACT Group. How Hyperprolactinemia Affects Sexual Function in Patients Under Antipsychotic Treatment. J Clin Psychopharmacol. 2016 Oct;36(5):422-8. PubMed PMID: 27433851.


Hyperprolactinemia is common with some antipsychotic medications—especially those that are potent blockers of dopamine 2 receptors.

This study evaluated sexual dysfunction in patients on a stable dose of antipsychotic medication.


This was a cross-sectional study; patients were not followed up..

The study included subjects between 18 and 55 years of age.

They had a “psychotic spectrum” diagnosis and were being treated in a variety of outpatient or inpatient settings.

Psychiatric rating scales, a questionnaire about sexual functioning, and a hormone panel were done.


101 patients (30 women and 71 men) participated in the study.

Hyperprolactinemia was present in 71% of patients.

Persons who had hyperprolactinemia were statistically significantly more likely to have sexual dysfunction (79% versus 52%).

Looked at in the opposite direction, persons who had sexual dysfunction had statistically higher mean levels of serum prolactin.

The relationship between hyperprolactinemia and sexual dysfunction was present in both males and females.

When we look at subgroups of patient, interesting findings are seen and are shown in the table below. All findings in the table were statistically significant.







Only prolactin-raising antipsychotics (risperidone, haloperidol, amisulpiride)



Only prolactin-sparing antipsychotics (aripiprazole, clozapine)



Aripiprazole alone



Aripiprazole plus another antipsychotic





Sexual dysfunction and hyperprolactinemia were significantly related.

The prevalence of both hyperprolactinemia and of sexual dysfunction was higher than has been found in previous studies.

Clinical Commentary

Note that because this was a cross-sectional study, cause and effect relationships cannot be determined. Association between two variables does not necessarily mean that one is causing the other.

The prevalence of hyperprolactinemia was very high in this study (71%) and higher than in previous studies. Even though the exact prevalence of hyperprolactinemia will depend on the population studied, clinicians need to appreciate that hyperprolactinemia is very common in persons taking an antipsychotic medication like risperidone or haloperidol (potent D2 receptor blockers).

I think that hyperprolactinemia is under-recognized in clinical settings unless there are obvious clinical effects like galactorrhea or gynecomastia that, of course, occur in a minority of patients.

Hyperprolactinemia is believed to be associated with various long-term risks (e.g., osteoporosis, worsening of prolactin-sensitive tumors).

Patients who realize that, for whatever reason, their sexual functioning is worse when they are on the antipsychotic are at high risk of non-adherence to the medication.

The findings of this study suggest that we should consider checking serum prolactin in persons who develop sexual dysfunction after starting an antipsychotic.

If hyperprolactinemia is present, we should consider switching to an antipsychotic with a lower potential for causing hyperprolactinemia or, if clinically indicated, adding a medication that may reverse the hyperprolactinemia.

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Are neurofeedback and physical exercise alternatives to stimulants for ADHD?

Geladé et al. Behavioral Effects of Neurofeedback Compared to Stimulants and Physical Activity in Attention-Deficit/Hyperactivity Disorder: A Randomized Controlled Trial. J Clin Psychiatry. 2016 Oct;77(10):e1270-e1277. PubMed PMID: 27631143.


There is continuous interest in alternatives to stimulant medication for the treatment of Attention-Deficit Hyperactivity Disorder (ADHD), especially in children and adolescents.

One of these is EEG neurofeedback. Children with ADHD are believed to have more theta (4 to 7 Hz) activity and less beta (13 to 20 Hz) activity. Greater beta activity is associated with alertness. EEG neurofeedback provides visual or auditory feedback about the theta/beta ratio and this feedback helps children learn to maintain greater alertness.

Of three previous randomized, controlled trials comparing neurofeedback to medication, two trials reported neurofeedback and medication to be equally efficacious and one reported that medication was more efficacious than neurofeedback. Thus, the question of whether neurofeedback is as efficacious as medication remained uncertain.

This study, therefore, aimed to compare the efficacy of EEG neurofeedback versus methylphenidate


This was a randomized, controlled trial.


The 112 participants were children aged 7 to 13 years who had a diagnosis of ADHD.


The three treatment groups were methylphenidate, EEG neurofeedback, and physical exercise.


  1. The methylphenidate was titrated up to the optimal, individualized dose for each patient. Short-acting methylphenidate 5 to 20 mg twice daily (i.e., 10 to 40 mg/day) was given at breakfast and lunch. Each of the doses was tried for a week and the “optimal” dose was identified and then continued for the rest of the duration of the study.

  2. The EEG neurofeedback was comprised of theta/beta training on the vertex of the head.


  1. The physical exercises were of moderate to vigorous intensity. Physical exercise was used as a plausible control intervention to control for nonspecific effects like increased monitoring and attention to the child. The number (about 30 sessions) and duration of the EEG neurofeedback and physical exercise sessions were approximately equal.


The children were evaluated through parent and teacher ratings using two questionnaires:


  1. The Strengths and Difficulties Questionnaire (SDQ), and

  2. The Strengths and Weaknesses of ADHD Symptoms and Normal Behavior (SWAN)   


Parents reported improvement on both the questionnaires for children in all three of the treatment groups.

Only in looking specifically at the SWAN Inattention scale, as reported by the parents, children who received methylphenidate had statistically significantly more improvement than children who received either EEG neurofeedback or physical exercise.

On the questionnaires filled out by the teachers, on the other hand, the ADHD symptoms improved on all the measures in children receiving methylphenidate but not in children receiving EEG neurofeedback or physical exercise.

The authors speculated that the reason for the discrepancy in parents’ and teachers’ ratings may be because the parents needed to be actively involved in the neurofeedback or physical exercise. The teachers had no active role in this. Therefore, the parents were more likely to be subject to an expectation bias, i.e., expecting the treatment to work.


For ADHD symptoms in children, individualized treatment with methylphenidate was more efficacious compared to EEG neurofeedback or physical exercise.

Clinical Commentary

Alternatives to medication, such as neurofeedback, are understandingly appealing to parents. However, clinicians making treatment recommendations should be clear that despite the availability of various other interventions, stimulant treatment remains the most effective treatment for symptoms of ADHD in children.

It is, of course, possible that EEG neurofeedback or physical exercise when added to stimulant medication may have additional benefits though this should not be assumed to be true.

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Is pregabalin another potential treatment for generalized anxiety disorder?

Generoso et al. Pregabalin for generalized anxiety disorder: an updated systematic review and meta-analysis. Int Clin Psychopharmacol. 2016 Sep 16. [Epub ahead of print] PubMed PMID: 27643884.


Generalized anxiety disorder or GAD is a common and chronic disorder that is associated with considerable suffering and functional impairment.

Although treatments are available, only about half the patients respond adequately and so, newer treatment options are needed.

Pregabalin has been evaluated in several clinical trials as a potential treatment for GAD.

This paper reports on a meta-analysis of clinical trials to evaluate the efficacy of pregabalin for GAD.


Only randomized, placebo controlled trials were included.

A systematic search of the literature was done to identify relevant studies.

A meta-analysis was done to combine the results of the studies.


Eight randomized, placebo-controlled trials that included about 2300 patients were included in this meta-analysis.

Combining the results of these studies, pregabalin was found to be statistically significantly more efficacious than placebo for the treatment of GAD.

How substantial was the efficacy? One way to evaluate this is by describing the Effect size; it was about 0.4, which indicates a small-to-moderate effect size.

Many of the studies included a benzodiazepine as a comparator. There was no statistically significant difference in the efficacy of pregabalin and the benzodiazepine in treating GAD.

What about tolerability? There was no significant difference between the number of subjects discontinuing treatment in the pregabalin and placebo groups.


Pregabalin was efficacious as a treatment for GAD and well-tolerated as indicated by the low rate of discontinuing the medication.

Clinical Commentary

Pregabalin is available in the US with the brand name Lyrica and has FDA indications for neuropathic pain, adjunctive treatment of partial onset seizures, and fibromyalgia.

If it is used for GAD, the use would be considered off-label.

Also, currently it is available in the US as a branded product only. Its cost is a little more than that of brand name antidepressants, which are also used off label to treat GAD.

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Another treatment option for clozapine-induced hypersalivation

Kreinin et al. Double-Blind, Randomized, Placebo-Controlled Trial of Metoclopramide for Hypersalivation Associated With Clozapine. J Clin Psychopharmacol. 2016 Jun;36(3):200-5. PubMed PMID: 27028980.


Hypersalivation is a common and distressing adverse effect of treatment with clozapine. It often leads to discontinuation of treatment.

While some treatment options exist, they are not effective in all patients.

Metoclopramide is a dopamine D2 antagonist, 5-HT3 antagonist, and 5-HT4 agonist that is used for the treatment of nausea/vomiting.

Metoclopramide causes dry mouth as an adverse effect in about 10% of patients.

This clinical trial aimed to evaluate the efficacy of metoclopramide for the treatment of clozapine-induced hypersalivation.


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

58 patients were enrolled who had the following characteristics:

1. Diagnosis of schizophrenia or schizoaffective disorder

2. Being treated with clozapine for at least two months

3. Significant nocturnal hypersalivation as defined on a rating scale.

The subjects were randomized to receive either metoclopramide or placebo for 3 weeks.

Doses of other medications were kept constant during the study.

Metoclopramide was started at 10 mg/day at 8 pm. If needed, after one week, the dose was increased to 10 mg at 8 am and 8 pm. After another week, if needed, the dose was increased to 10 mg three times a day. Thus, the daily dose was 10 to 30 mg/day.


Using rating scales for hypersalivation and for drooling, metoclopramide was statistically significantly more efficacious than placebo.

The patients treated with metoclopramide were judged to be substantially improved by the investigators who were blinded to the treatment the patients were receiving.

67% of patients who received metoclopramide versus 29% of patients who received placebo had either a significant decrease or complete resolution of the hypersalivation. That is a 38% difference, which is huge.

No adverse effects were reported.


Metoclopramide was an effective and well-tolerated treatment for clozapine-induced hypersalivation.

Clinical Commentary

In patients treated with clozapine, hypersalivation should be treated and not ignored, not only to reduce personal distress but also to reduce discontinuation of treatment.

We must keep in mind that clozapine is a very important medication given its unique role in treating schizophrenia that has not responded to other antipsychotic medications. Given the lack of adequate alternatives to clozapine, it is particularly important to try to keep the patient on this medication.

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Should we be identifying binge eating in persons with mood disorders?

Woldeyohannes et al. Binge eating in adults with mood disorders: Results from the International Mood Disorders Collaborative Project. Obes Res Clin Pract. 2016 Sep - Oct;10(5):531-543. PubMed PMID: 26508286.


Binge-eating disorder is recognized in DSM-5 as a distinct mental disorder.

But binge-eating most commonly occurs along with another mental disorder.

This study aimed to describe binge eating as it occurs in persons with major depressive disorder or bipolar disorder.


The study used pre-existing data on about 630 adult patients with either major depressive disorder or bipolar disorder who had participated in a large, multicenter study of mood disorders.


About 21% of patients with a mood disorder were found to have had binge-eating behavior.


The percentage of persons with bipolar disorder who had binge-eating behavior was greater than that for persons with major depressive disorder (25% versus 16%).


Did presence of binge-eating have any implications for the mood disorder? Persons with the mood disorder who also had binge-eating had:


  • greater severity of anxiety

  • greater severity of neuroticism

  • higher rates of both lifetime and current substance dependence

  • higher rates of Attention-Deficit Hyperactivity Disorder

  • higher rates of being obese (50% versus 26%).   


Binge eating was common among adult patients with a bipolar disorder or major depressive disorder who were being treated in a tertiary care center.

Persons who have comorbid binge eating are more likely to have various other comorbidities indicating greater illness complexity.

Clinical Commentary

We should probably screen persons with a mood disorder for presence of binge eating.

Due to greater comorbidities and complexity, persons with both a mood disorder and binge eating may require more careful evaluation, treatment, and follow up.

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Rajnish Mago, MD
Medical Editor, GME Research Review

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