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Issue 58, Feb 2017
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Psychiatric Medications: Who Takes What?

Moore TJ, Mattison DR. Adult Utilization of Psychiatric Drugs and Differences by Sex, Age, and Race. JAMA Intern Med. 2016 Dec 12. [Epub ahead of print] PubMed PMID: 27942726.


There is limited data on the prevalence of use of various psychotropic medications in the general population.


The study used existing data from a survey done in the USA in 2013.

Prescription records on a systematic sample of about 37,000 adults (18 to 85-years-old) were included.


Overall, 17% of adults in the US reported filling at least one prescription for a psychiatric medication:

Antidepressants 12%

Anxiolytics, sedatives, and hypnotics   8%

Antipsychotics   1.5%


Filling a prescription for a psychiatric medication was more likely in:

 1. Women (21%) than men (12%)

2. White persons (21%) than Blacks (10%), Hispanics (9%), or Asians (5%).

3. Older persons (60 to 85 years; 25%) than younger persons (18 to 39 years; 9%)


These differences were based on differences in prescriptions for antidepressants and for anxiolytics/sedatives/hypnotics. However, prescriptions for antipsychotics did not differ across any demographic group.


84% of the use of a psychiatric medication was “long-term” (defined as either filling at least three prescriptions in that year or having started taking that medication in 2011, two years prior to the survey).


Can you guess which psychiatric medications were used by the greatest number of persons in the US in 2013? In descending order, these were:

  1. Sertraline

  2. Citalopram

  3. Alprazolam

  4. Zolpidem

  5. Fluoxetine

  6. Trazodone

  7. Clonazepam

  8. Lorazepam

  9. Escitalopram

  10. Duloxetine


One in six adults in the US reported filling a prescription for a psychiatric medication in 2013.

There were big (two- to three-fold) differences in use of psychiatric medications in some demographic groups compared with others.

Clinical Commentary

To me, the most concerning thing in these data is the common use of alprazolam and zolpidem, especially keeping in mind that the vast majority of the use of psychiatric medications was “long-term”.

I also cannot help wondering what percentage of these millions of persons taking an antidepressant or an anxiolytic have a biological condition for which we know that the medications can be very useful.

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Do SSRIs increase the risk for spontaneous intracranial hemorrhage?

Renoux C, Vahey S, Dell'Aniello S, Boivin JF. Association of Selective Serotonin Reuptake Inhibitors With the Risk for Spontaneous Intracranial Hemorrhage. JAMA Neurol. 2016 Dec 5. [Epub ahead of print] PubMed PMID: 27918771.

Commentary in: Hemphill JC 3rd. Selective Serotonin Reuptake Inhibitors and Intracranial

Hemorrhage: Deriving Clinical Relevance From an Epidemiologic Association. JAMA

Neurol. 2016 Dec 5. [Epub ahead of print] PubMed PMID: 27918755.


SSRIs are known to inhibit platelet aggregation and increase the risk of bleeding.


This study evaluated whether:

1. SSRIs increase the risk for spontaneous intracranial hemorrhage

2. This risk is linked to how strongly the antidepressant inhibits serotonin reuptake, and

3. The use of an antithrombotic along with the SSRI modifies this risk.


A population-based cohort study was done in subjects 18 years or older.

Data in a clinical practice research database from more than 650 general practices in the United Kingdom was used.

Subjects who developed a first instance of intracranial hemorrhage (Cases) were identified.

They were matched to up to 30 Control individuals.

Cases and Controls were compared for current use of an SSRI versus a tricyclic antidepressant.

In addition, Cases and Controls were compared for use of a strong versus a weak inhibitor of serotonin reuptake. Strong inhibitors of serotonin reuptake were clomipramine, duloxetine, fluoxetine, paroxetine, and sertraline.


Nearly 1.4 million persons who used an antidepressant were identified.

The mean age of the subjects was 48 years and about two-thirds were female.

During a variable follow up period, 3036 Cases of intracranial hypertension were identified and included in the study along with nearly 90,000 Controls to whom they were matched.

Current SSRI use was associated with a slightly increased risk for intracranial hemorrhage compared to use of a tricyclic antidepressant (relative risk 1.2).

The increased risk was highest in the first 30 days of taking the antidepressant (relative risk 1.4).

The risk was more with strong inhibitors of serotonin reuptake compared to weaker inhibitors (relative risk 1.25).

When a serotonin reuptake inhibitor was used along with an antithrombotic, the risk was further increased (relative risk 1.7).


The use of a serotonin reuptake inhibitor is associated with an increased risk for spontaneous intracranial hemorrhage.

This risk is greater in the first 30 days of starting the antidepressant, with strong inhibitors of serotonin reuptake, and if the person is also taking an oral anticoagulant.

Clinical Commentary

Risks associated with SSRIs become important due to the extraordinary number of people prescribed these medications. What I mean by that is that even if there is a small risk, when you multiply that by the large number of persons taking the medication, a significant number of persons may be affected.

The other reason why the topic of this study is particular important is that SSRIs are often prescribed to persons who have had a stroke or are at risk of having a stroke.

An accompanying Editorial (Hemphill, 2016) noted that there are many ongoing clinical trials of using SSRIs in poststroke recovery. Many persons with stroke are treated with antiplatelet agents or anticoagulants, so these patients are at higher risk for intracranial bleeding than the general population.

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Physician, heal thyself

Rotenstein LS, Ramos MA, Torre M, Segal JB, Peluso MJ, Guille C, Sen S, Mata DA. Prevalence of Depression, Depressive Symptoms, and Suicidal Ideation Among Medical Students: A Systematic Review and Meta-Analysis. JAMA. 2016 Dec 6;316(21):2214-2236. PubMed PMID: 27923088.

Commentary in: Slavin SJ. Medical Student Mental Health: Culture, Environment, and the Need for Change. JAMA. 2016 Dec 6;316(21):2195-2196. PubMed PMID: 27923076.


Several studies have suggested that medical students are at high risk for depression and suicidal ideation.

This study combined data from previous studies on this topic.


A systematic search of multiple databases was done to identify relevant studies.

Only studies that were published in the peer-reviewed literature and that used validated assessment methods were included. Studies published in languages other than English were not excluded.

Three investigators independently extracted information from the papers.

The data from the studies were combined using meta-analysis.


167 cross-sectional studies including a total of nearly 117,000 subjects and 16 longitudinal studies including nearly 5800 subjects were included in these analyses.

In all but one study, the data were obtained using self-report questionnaires.

The overall pooled prevalence of depressive symptoms or depression was 27%.

No increase in the prevalence of depressive symptoms over the years during which these studies were done was found.

There were nine longitudinal studies with nearly 2500 medical students that assessed depressive symptoms before and during medical school. In these studies, the median increase in depressive symptoms from before to during medical school was 14%.

Would you predict that the increase in depressive symptoms would be greater in studies that included only preclinical students or in studies that included only clinical students?  This meta-analysis found that the increase in symptoms was similar in both types of medical students.

Do medical students who screen positive for “depression” seek psychiatric treatment?  Only 16% of them did.

Information about suicidal ideation was obtained from 24 cross-sectional studies that included about 21,000 subjects from 15 countries. All but one of these studies used a self-report questionnaire to identify suicidal ideation.

Overall, 11% of the medical students who participated reported suicidal ideation.


27% of medical students who participated in these studies reported depressive symptoms and 11% reported suicidal ideation.

More research is needed into how to prevent and treat depression and suicidality in medical students.

Clinical Commentary

An accompanying editorial (Slavin, 2016) asks the troubling question: What is it about the culture of medicine and of medical education that has allowed this problem to remain unaddressed for so long and for studies of interventions to lag so far behind the number of studies of the nature of the problem?

Medical school can be a stressful experience. Most importantly, systemic changes are needed to make the training experience less stressful.

In my opinion, given the high numbers described in this study, all medical students should be screened once a year for presence of depression, anxiety, sleep disturbances, etc. Those who screen positive should be given access to confidential resources for help.

Persons who have suffered from clinical depression or who are otherwise predisposed to mental health problems may require additional screening and interventions.

Perhaps all medical students should regularly get training in self-care and stress management including support groups, meditation, etc.

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Do persons with bipolar disorder have comorbid anxiety disorders while euthymic?

Pavlova B, Perlis RH, Mantere O, Sellgren CM, Isometsä E, Mitchell PB, Alda M, Uher R. Prevalence of current anxiety disorders in people with bipolar disorder during euthymia: a meta-analysis. Psychol Med. 2016 Dec 20:1-9. [Epub ahead of print] PubMed PMID: 27995827.


It is generally known that anxiety disorders commonly occur in persons with bipolar disorder.

However, do anxiety disorders also occur when these persons are euthymic, that is, free of major mood episodes?

This study evaluated what proportion of persons with bipolar disorder (currently euthymic) also meet diagnostic criteria for any anxiety disorder.


A meta-analysis of studies on the topic was performed.

All anxiety disorders defined in the DSM III or DSM IV were included: panic disorder, agoraphobia, social anxiety disorder, generalized anxiety disorder, specific phobia, obsessive-compulsive disorder, post-traumatic stress disorder, and anxiety disorder not otherwise specified.

Ten studies with a total of about 2100 subjects with bipolar disorder were included.

Of persons with bipolar disorder who were currently euthymic, 35% (i.e., about one-thirds) met diagnostic criteria for at least one anxiety disorder.

When persons with bipolar disorder (currently euthymic) were compared to population controls, an almost five-fold increase in the anxiety disorders was found in persons with bipolar disorder even when they were euthymic.


Anxiety disorders are common in persons with bipolar disorder even when their mood is adequately controlled.

Clinical Commentary

Comorbidity is often missed. We should make it a point to routinely and systematically evaluate persons with bipolar disorder for the presence of comorbid anxiety disorders when the mood episodes are relatively well-controlled, i.e, they are euthymic.

If an anxiety disorder is identified, specific treatment for it may be indicated because these comorbid anxiety disorders may not improve simply by treating the bipolar disorder.

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How well do alpha2 agonists work for opioid withdrawal?

Gowing L, Farrell M, Ali R, White JM. Alpha₂-adrenergic agonists for the management of opioid withdrawal. Cochrane Database Syst Rev. 2016 May 3;(5):CD002024. PubMed PMID: 27140827.


This study aimed to assess the efficacy of alpha2-adrenergic agonists (clonidine, lofexidine, guanfacine, tizanidine) for treating acute opioid withdrawal.


This was a systematic review from the Cochrane Collaboration, an international effort that uses standardized, rigorous methodology to systematically review the data from randomized, controlled clinical trials evaluating various interventions.

As is characteristic of the systematic reviews from the Cochrane Collaboration, a thorough search of the literature was done to identify relevant studies and a reproducible methodology was used to extract the data.

Randomized controlled trials were included that compared an alpha2-adrenergic agonist to a control treatment for managing the signs and symptoms of opioid withdrawal in persons who were opioid dependent.


26 randomized, controlled clinical trials with a total of about 1700 subjects were included.


Alpha-2 adrenergic agents were compared to:

1. Placebo (six studies)

2. Methadone taper, i.e., methadone with gradual reduction in dose (12 studies)

3. Another alpha2-adrenergic agonist (five studies), or

3. Symptomatic medications only (four studies).


How did alpha2-adrenergic agonists compare to placebo?

1. They were found to be more efficacious than placebo in reducing the risk of severe opioid withdrawal (risk ratio 0.3).

2. Persons treated with an alpha2-adrenergic agonist were almost twice as likely to complete treatment as persons treated with a placebo (relative risk of nearly 2).


How did alpha2-adrenergic agonists compare to tapering doses of methadone?

1. There was no statistically significant difference between alpha2-adrenergic agonists and reducing doses of methadone in the peak withdrawal severity or in the likelihood of severe withdrawal.

2. The signs and symptoms of withdrawal occurred and resolved earlier with alpha2-adrenergic agonists than with a methadone taper.

3. The duration of treatment was longer with the methadone taper than with alpha2-adrenergic agonists.

4. However, adverse effects including hypotension were more likely with alpha2-adrenergic agonists than with the methadone taper (relative risk 1.9).  


How did one alpha2-adrenergic agonist compare with another?

 1. Data comparing the different alpha2-adrenergic agonists were relatively weak. One was not shown to be more efficacious than the other.

 2. The available data suggested that lofexidine does not reduce blood pressure to the same extent as clonidine.


Clonidine and lofexidine are efficacious for the management of opioid withdrawal.

Clonidine, lofexidine, and a methadone taper appeared to be equally efficacious.

However, the methadone taper was associated with fewer adverse effects than alpha2-adrenergic agonists.

Lofexidine was associated with fewer adverse effects than clonidine.

Clinical Commentary

The use of alpha2-adrenergic agonists as the sole intervention is a viable alternative to a methadone taper. However, they are not approved by the FDA for this purpose, so this would be off-label use.

Note that lofexidine is not currently available in the US but attempts to obtain FDA-approval are underway.


Note that this systematic review does not cover other treatment options like:

1. A combination of a methadone taper and an alpha2-adrenergic agonist.

2. Opioid antagonists to induce withdrawal with minimal sedation or under heavy sedation or anesthesia.

3. Alpha2-adrenergic agonist plus buprenorphine.

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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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