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Issue 55, Nov 2016
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Do hypnotic medications lead to suicide?

McCall et al. Hypnotic Medications and Suicide: Risk, Mechanisms, Mitigation, and the FDA. Am J Psychiatry. 2016 Sep 9 [Epubahead of print] PubMed PMID: 27609243.

Background

It is known that insomnia is associated with an increased risk for suicide.

But do hypnotic medications lead to an increased risk of suicide as has been previously claimed?

This paper reviewed published data for and against the claim that hypnotic medications may lead to an increased risk of suicide. 

Methods

A literature search was done that included PubMed and Web of Science, but not other databases. Not a thorough search.

Papers related to suicide and any of the modern FDA-approved hypnotics were identified.

In addition, the FDA’s website was searched for post-marketing safety reviews about these hypnotics.

Lastly, the FDA was contacted for detailed case reports for hypnotic-related suicide deaths that had been reported through the FDA’s Adverse Event Reporting System.

Results

Epidemiological research shows a statistical association between taking hypnotic medications and having an increased risk for suicide.

However, none of these studies adequately controlled for presence of depression or other psychiatric disorders.

Another way in which hypnotics may be associated with an increased risk of suicide is that the benzodiazepine receptor agonist hypnotics (the so-called Z drugs) can cause parasomnias, which in rare cases can lead to suicidal ideation or suicidal behavior. And this can occur in persons who were not previously known to be suicidal. 

Conclusions

Use of hypnotic medications is associated with suicidal ideation, but it is not known if the medications are the cause of the suicidal ideation. 

On the other hand, treatment of insomnia may reduce suicidality, though this has not been shown. 

Clinical Commentary

Psychiatric disorders are associated with a) use of hypnotics and b) an increased risk of suicide. Therefore, it is only to be expected that there will be an association between use of hypnotics and an increased risk of suicide. This doesn’t mean that the hypnotics are the cause of the increased risk of suicide. Association does not mean causality. You see why things like this are hard to research?

The Prescribing Information for temazepam, a benzodiazepine hypnotic notes: “In primarily depressed patients, worsening of depression, including suicidal thinking has been reported in association with the use of sedative/hypnotics.” Thus, clinicians need to be aware of the risk.

On the other hand, it is important to treat insomnia for many reasons including possible reduction in suicidality. However, let’s remember that cognitive-behavior therapy of insomnia (CBTi) is an effective alternative to hypnotic medications.

Patients prescribed one of the Z drugs should be carefully monitored for the emergence of any parasomnias and discontinuation of the medication may be needed if this happens. 

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The best two types of psychotherapy for panic disorder

Pompoli et al. Psychological therapies for panic disorder with or without agoraphobia in adults: a network meta-analysis. Cochrane Database Syst Rev. 2016 Apr 13;4:CD011004. PubMed PMID: 27071857.

Background

Panic disorder is common; it has a lifetime prevalence of 1% to 4%.

Psychological therapy (with or without medication) is accepted as a first-line treatment for panic disorder.

But are some psychological treatments better than others for panic disorder? 

This review is from the Cochrane Collaboration, an international effort to systematically and verifiably combine and summarize research on various treatments in medicine. 

Methods

In order to answer this question, in this review the authors combined the findings from various studies—they did a meta-analysis—of eight different types of psychotherapies for panic disorder.

They looked at studies on panic disorder with or without agoraphobia but only at randomized, controlled trials in adults.

The search of the literature was extremely thorough.

So, what were these eight psychological therapies for panic disorder looked at in this review?

  1. Psychoeducation
  2. Supportive psychotherapy
  3. Physiological therapies (e.g., breathing retraining, relaxation training, biofeedback)
  4. Behavior therapy
  5. Cognitive therapy
  6. Cognitive behavior therapy
  7. “Third-wave” cognitive behavior therapy (e.g., mindfulness-based cognitive therapy, acceptance and commitment therapy)
  8. Psychodynamic therapy.

Both individual and group formats were included but the therapies had to be administered face-to-face, i.e., not online.

As is unfortunately common in psychotherapy clinical trials, the control or placebo conditions were not that great. 

Results

Sixty clinical trials were included, of which 54 studies with a total of about 3000 patients in them were combined quantitatively.

For the important outcome measure of short-term remission, there were 32 studies for cognitive-behavior therapy, 12 studies for behavior therapy, 10 studies for physiological therapy, 3 studies for cognitive therapy, 3 studies for supportive psychotherapy, and 2 studies for psychodynamic therapy.

There were several methodological problems with the studies.

Overall, psychological therapies were more efficacious than waitlist control conditions. So, psychotherapy does work for panic disorder.

Cognitive-behavior therapy appeared to be better than some of the other psychotherapies. Psychodynamic therapy and supportive psychotherapy also seemed to be more efficacious than other interventions.

In the long term, cognitive behavior therapy and psychodynamic therapy showed the highest level of remission/response. 

Conclusions

The studies included in this meta-analysis had various limitations. There is no high-quality research to clearly support one psychological therapy over the others for the treatment of panic disorder with or without agoraphobia in adults.

However, there was some data to suggest that cognitive behavior therapy was somewhat superior to other therapies.

There was also some data to show that psychodynamic therapy was efficacious.

However, we don’t know whether either cognitive behavior therapy or psychodynamic therapy is more efficacious than the other.

Interestingly, among the different psychotherapies, psychodynamic therapy had the lowest short-term drop out rate

Behavior therapy did not appear to be a valid alternative to cognitive behavior therapy as a first-line treatment for patients with panic disorder with or without agoraphobia.

Clinical Commentary

Psychological treatments for panic disorder need to be used much more widely than they are at this time. We should keep in mind that medications may produce only partial benefit and that they need to be taken long term. Also, many patients with panic disorder are very sensitive to adverse effects of medication and are reluctant to take medications.

Whether we do the therapy ourselves or refer the person to a therapist specialized in that form of psychotherapy, it is important for us to know which therapies have been shown to be better than others.

I think that those trained in psychodynamic therapy will be pleased to find research support for psychodynamic treatment of panic disorder with or without agoraphobia. The sample size for psychodynamic psychotherapy was only about 100 patients which limits the generalizability of the findings. Unfortunately, it is common to find the term “evidence-based psychotherapy” to mean only or mainly cognitive behavior therapy. 

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Beyond Viagra: What are other options for erectile dysfunction?

Hatzimouratidis et al. Pharmacotherapy for Erectile Dysfunction: Recommendations From the Fourth International Consultation for Sexual Medicine (ICSM 2015). J Sex Med. 2016 Apr;13(4):465-88. PubMed PMID: 27045254.

Background

The literature on treatment of erectile dysfunction was reviewed by one of the organizations of specialists in sexual medicine and recommendations were issued in this paper.

Mental health professionals often encounter erectile dysfunction in our patients. We either treat this problem ourselves or refer to a specialist. Either way, we should at least be aware of these guidelines. 

Methods

A review of the literature was done by experts on the topic who were members of a committee appointed for this purpose. The committee then critically analyzed and discussed the research evidence.

Levels of evidence (LE) and grades of recommendations (GR) were assigned to the different recommendations. A higher level of evidence (e.g., LE = 1) and grade of recommendation (e.g., GR = A) means that the experts are surer about that recommendation. 

Results

The committee provided the following 10 main recommendations:

1. Phosphodiesterase type 5 (PDE-5) inhibitors are effective, safe, and well-tolerated for the treatment of men with erectile dysfunction (LE = 1, GR = A).

2. There are no significant differences in efficacy, safety, and tolerability among the PDE-5 inhibitors (LE = 1, GR = A).

3. PDE-5 inhibitors are first-line therapy for most men with erectile dysfunction who do not have a specific contraindication to their use (LE = 3, GR = C).

4. Intracavernosal injection therapy with alprostadil is an effective and well-tolerated treatment for men with erectile dysfunction (LE = 1, GR = A).

5. Intracavernosal injection therapy with alprostadil should be offered to patients as second-line therapy for erectile dysfunction (LE = 3, GR = C).

6. Intraurethral and topical alprostadil are effective and well-tolerated treatments for men with erectile dysfunction (LE = 1, GR = A).

7. Intraurethral and topical alprostadil should be considered second-line therapy for erectile dysfunction if this treatment is available to the patient (LE = 3, GR = C).

8. Dose titration of PDE-5 inhibitors to the maximum tolerated dose is strongly recommended because it increases efficacy and satisfaction from treatment (LE = 2, GR = A).

9. Treatment selection and follow-up should address the psychosocial profile and the needs and expectations of a patient for his sexual life. Shared decision making with the patient (and his partner) is strongly recommended (LE = 2, GR = A).

10. Counterfeit medicines are potentially dangerous. It is strongly recommended that physicians educate their patients to avoid taking any medication from unauthorized sources (LE = 2, GR = A). 

Conclusions

PDE-5 inhibitors remain a first-line treatment option because of their excellent efficacy and safety profile.

Intracavernosal injections are also an established treatment modality, but are second line for obvious reasons.

Intraurethral and topical alprostadil are alternative treatment options that are less invasive than intracavernosal injections. 

Clinical Commentary

I hope that many mental health professionals have enough training to be able to prescribe PDE-5 inhibitors for two reasons. The number of men with erectile dysfunction is too large for specialists to be able to see them. Also, antidepressant medications lead to erectile dysfunction in many men who take them and PDE-5 inhibitors have been shown to be an effective treatment for these patients as well.

Regarding the other treatments, mental health professionals won’t prescribe them, but we should be aware of them so that we can appropriately guide our patients to seek these treatments out when needed. 

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Can we give stimulants to persons with bipolar disorder?

Viktorin et al. The Risk of Treatment-Emergent Mania With Methylphenidate in Bipolar Disorder. Am J Psychiatry. 2016 Oct. PubMed PMID: 27690517.

Background

Previous literature had not answered the question of whether the risk of mania in persons with bipolar disorder is different when methylphenidate is taken with or without a mood stabilizer. 

Methods

About 2300 persons with bipolar disorder who had started on methylphenidate during a defined period were identified in Swedish national registries.

These persons were divided into two groups: those who were or were not taking a mood stabilizer at the time that they started methylphenidate.

Attempts were made to statistically adjust for other clinical features to the extent possible in a database without directly evaluating the patients.  

Two outcomes were looked for—hospitalization for mania OR addition of a new mood stabilizing medication.

These two outcomes were evaluated at two time points—0 to 3 months after starting methylphenidate and 3 to 6 months after starting methylphenidate. 

Results

Patients on methylphenidate without a mood stabilizer had an increased risk of mania within the first 3 months after starting the methylphenidate and this increased risk persisted in the subsequent 3 months as well.

Patients with bipolar disorder who were started on methylphenidate but were also on a mood stabilizer had a lower risk of mania.

The authors also analyzed the data by looking only at hospitalizations for mania (not addition of a new mood stabilizer) and the results were similar to ones described above. 

Conclusions

No evidence was found for an increased risk of mania after addition of methylphenidate in persons with bipolar disorder who were taking a mood stabilizer at the time that methylphenidate was added. 

Clinical Commentary

There are many patients (up to 20%) with bipolar disorder who also have ADHD. In these patients, effective mood stabilizer treatment should be initiated first, but these patients need not be deprived of the benefits of stimulant treatment.

The flip side of this is that before starting stimulant monotherapy in a person with ADHD, we should make sure that we have carefully ruled out bipolar disorder. 

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Combining a stimulant and guanfacine may reduce side effects

Sayer et al. Acute and Long-Term Cardiovascular Effects of Stimulant, Guanfacine, and Combination Therapy for Attention-Deficit/Hyperactivity Disorder. J Child Adolesc Psychopharmacol. 2016 Aug 2. [Epub ahead of print] PubMed PMID: 27483130.

Background

In the October issue of GME Research Review (http://www.gmeded.com/content/october-2016-research-review), we discussed an important clinical trial of dexmethylphenidate extended-release, guanfacine immediate-release, and their combination for the treatment of ADHD.

This paper is data from the same study but focused (no pun intended) on cardiovascular adverse effects with these 3 treatments. 

Methods

This was a randomized, double-blind, clinical trial in 207 children aged 7 to 14 years.

The children were given one of three treatments for 8 weeks:

1. Dexmethylphenidate extended-release 5 to 20 mg/day

2. Guanfacine immediate-release 1 to 3 mg/day

3. The combination of both of the above.

The medications were titrated to optimal response.

Heart rate, systolic blood pressure, diastolic blood pressure, and electrocardiograms were assessed at baseline, at end of blinded optimization, and over a 1-year open-label maintenance phase.

Results

During acute titration, guanfacine immediate-release was associated with a decrease in heart rate, systolic blood pressure, and diastolic blood pressure.

Dexmethylphenidate, on the other hand, was associated with an increase in heart rate, systolic blood pressure, diastolic blood pressure, and in the QTc interval.

The combination of the two medications was associated with an increase in diastolic blood pressure, but it had no effects on heart rate, systolic blood pressure, or the QTc interval.

During the maintenance phase, decreases in heart rate associated with guanfacine and the increases in systolic blood pressure associated with dexmethylphenidate both returned to baseline values.

There were no discontinuations due to cardiovascular adverse events.

Conclusions

The changes in cardiovascular parameters associated with either monotherapy during the acute phase were those that were expected. However, they tended to return to baseline over time.

The cardiovascular changes with the combination of dexmethylphenidate and guanfacine were intermediate between those with either treatment alone.

The authors concluded that the combination treatment might reduce the cardiovascular risks associated with either of the monotherapies. 

Clinical Commentary

The combination of a stimulant and an alpha 2 agonist (guanfacine or clonidine) is an interesting one because the alpha 2 agonist can counteract not only the cardiovascular adverse effects, as shown by this study, but also some other adverse effects of the stimulant, e.g., insomnia.

Perhaps this combination should be considered more often? 

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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]


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