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Issue 56, Dec 2016
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Twelve symptoms that may help predict relapse of depression

Judd et al. A Brief Clinical Tool to Estimate Individual Patients' Risk of Depressive Relapse Following Remission: Proof of Concept. Am J Psychiatry. 2016 Nov 1;173(11):1140-1146. PubMed PMID: 27418380.


Our ability to predict relapse in persons with major depressive disorder is quite limited.

However, it is important to be able to identify those at higher risk of relapse so that energetic efforts can be focused on those persons.

This study aimed to determine whether certain symptoms still present in persons who have been in remission for at least 8 weeks after an episode of major depressive disorder can be used to predict their risk for relapse during the next 6 months.


The study used data from 188 patients with major depressive disorder who had participated in the NIMH-funded Collaborative Depression Study.

Persons who had at least one assessment with the Symptom Checklist-90 after at least 8 weeks of full remission from a depressive episode were included.

The Symptom Checklist-90 is a questionnaire that assesses for presence of 90 diverse psychological symptoms. 


Seventeen of the 90 items on the Symptom Checklist-90 were found to have some value in predicting whether or not the person would relapse in the subsequent 6 months.

These symptoms can be categorized as related to depression, anxiety, or psychological vulnerability.

From these 17, a set of 12 symptoms was identified that had the greatest ability to predict relapse versus non-relapse.

So, what are these 12 items of the Symptom Checklist-90?

  1. Feeling blocked in getting things done
  2. Feeling pushed to get things done
  3. Feeling tense or keyed up
  4. Having ideas/beliefs others do not share
  5. Feeling inferior to others
  6. Feeling low in energy or slowed down
  7. Feeling very self-conscious with others
  8. Headaches
  9. Crying easily

10. Feelings being easily hurt

11. Worrying too much about things

12. Trouble concentrating

Note: In the Symptoms Checklist-90, the symptoms are asked for exactly as stated above. No further details are provided to the subject.

To what extent did these symptoms predict relapse in these patients? The relapse rate was:

-       6% when none of the 12 symptoms were present

-       17% when 1 to 5 symptoms were present

-       34% when 6 to 9 symptoms were present, and

-       73% when 10 or more of these 12 symptoms were present.


A brief symptom scale of 12 symptoms may be used to identify persons who are at higher risk of relapse despite being in full remission from an episode of major depressive disorder. 

Clinical Commentary

Persons who have several of these 12 symptoms after being in full remission should probably be monitored more closely and receive additional interventions to reduce the risk of relapse.

Note that these 12 symptoms don’t necessarily have to represent residual symptoms of the depressive episode. In my opinion, as we ask our patients who are in remission about these 12 symptoms, we may identify comorbid anxiety disorders, personality disorders, executive dysfunction, etc. In addition to continued antidepressant treatment, management of these comorbid problems may help reduce the risk of relapse of major depressive disorder.

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Can modafinil be an alternative treatment for ADHD?

Wang et al. Modafinil for the treatment of attention-deficit/hyperactivity disorder: A meta-analysis. J Psychiatr Res. 2016 Oct 20;84:292-300. PubMed PMID: 27810669.


While various medications for ADHD are available, more than 30% of patients do not respond adequately to these treatments. More treatment options are, therefore, needed.

This paper reports on the first ever meta-analysis of studies of the efficacy and safety of modafinil in the treatment of children and adolescents with ADHD.


An extensive search of databases and clinical trial registries was done.

Five published short-term randomized, double-blind, placebo-controlled trials were identified.

Unpublished studies were not identified, which is an important limitation of this meta-analysis since we know that negative studies tend to not get published.


Five relevant clinical trials were found.

Compared to patients who received placebo, those who received modafinil showed statistically significantly greater improvement in scores on the ADHD Rating Scale-IV (both the Home and School version).

The effect size for modafinil was moderate-to-large.

Children and adolescents who received modafinil had a statistically significantly higher incidence of decreased appetite (relative risk 5 compared to placebo) and of insomnia (relative risk 6).

There was no clinically significant increase in the heart rate or blood pressure. 


Modafinil was efficacious for the treatment of ADHD in children and adolescents. 

Clinical Commentary

This meta-analysis is welcome because modafinil is being used off-label in clinical practice as a treatment for ADHD.

It should be noted that the modafinil is not simply another stimulant. It has multiple, complex pharmacological effects in the brain.

Potential advantages of modafinil over psychostimulants may be a lower liability for abuse and for cardiovascular adverse effects.

However, due to limited data, off-label status, cost, and difficulties with obtaining modafinil through health insurance, I recommend keeping modafinil as a second- or third-line treatment option. 

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Patients with panic disorder are at increased risk of cardiac disease

Caldirola et al. Is there cardiac risk in panic disorder? An updated systematic review. J Affect Disord. 2016 Apr;194:38-49. PubMed PMID: 26802506.


This paper reviewed the literature on the association between panic disorder and coronary artery disease, cardiac arrhythmias, cardiomyopathies, and sudden cardiac death.


A search of PubMed and bibliographies was done to identify relevant studies. 


Fourteen studies on coronary artery disease, 2 on cardiomyopathies, and 1 on cardiac arrhythmias were included.

When the coronary artery disease is identified (typically at age 50 or later), the rates of current panic disorder are relatively low.  This should not be surprising since panic disorder tends to occur at a younger age.

However, there was an association between having a lifetime history of panic disorder and having coronary artery disease.

In a prospective study, panic disorder was an independent risk factor for future acute myocardial infarction.

In addition, in some of the studies that did not find an association between current panic disorder and coronary artery disease, there was an association between coronary artery disease and:

  1. Past history of panic disorder
  2. Current agoraphobia, or
  3. Current subthreshold panic symptoms.

While less clear, the data also suggested an association between having panic disorder and having cardiac arrhythmias or cardiomyopathies.

The authors discussed potential mechanisms that may explain the association between panic disorder and cardiovascular disease. These may include physiological (e.g., autonomic dysregulation) and/or behavioral reasons (e.g., avoiding physical exercise). 


This review of the literature supported an association between panic disorder and cardiovascular disease. 

Clinical Commentary

It is important to note that association does not necessarily mean causation. The conclusion from this study should not be that panic disorder causes cardiovascular disease. To show causation, prospective cohort studies would be needed. That is, two groups of persons who did not have cardiovascular disease would be identified, one with and one without panic disorder. The two groups would then be followed up over time to see if the persons with panic disorder were more likely to develop cardiovascular disease than persons in the control group. In the present meta-analysis, 12 of the 17 studies used were cross-sectional rather than longitudinal.

A central strategy we employ in managing panic disorder is reassurance that it does not indicate the presence of cardiac disease. But these data indicate that this reassurance may not be entirely valid!

From the viewpoint of the mental health professional, an extremely important take-away from this study is that just because a person has panic disorder, it should not be assumed that any cardiovascular symptoms that occur are due to the panic disorder. This could lead to our failing to identify comorbid cardiovascular disease.

Further research into the exact nature of these associations between panic symptoms and cardiovascular disease may also guide prevention and treatment efforts. 

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How to know who will benefit from exercise for depression

Suterwala et al. Affect Following First Exercise Session as a Predictor of Treatment Response in Depression. J Clin Psychiatry. 2016 Aug;77(8):1036-42. PubMed PMID: 27561137.


In recent years, data from randomized controlled clinical trials have shown that aerobic exercise can be efficacious as an adjunctive treatment for major depressive disorder.

If response to a treatment could be predicted early on, this would reduce wasted time in trying that treatment.

This study used data from the National Institute of Mental Health-funded Treatment with Exercise Augmentation for Depression (TREAD) study to assess whether positive affect after the first exercise session predicts response to adjunctive exercise. 


In the TREAD study, 122 subjects with major depressive disorder were randomized to receive either a “public health dose” of exercise or a low dose of exercise (control condition) for 12 weeks. The term “public health dose” means that the exercise intensity and frequency was the same as is recommended for the general population.

Patients’ affect following the first exercise session was assessed using the Positive and Negative Affect Schedule (PANAS).

Note: This questionnaire is a simple instrument that consists of a list of 20 feeling words that may be positive (e.g., Interested, Enthusiastic, Determined) or negative (e.g., Upset, Distressed, Irritable). For each of the words, the subject is asked to indicate on a 1 to 5 scale to the extent to which s/he feels that way right now. Ten of the items are positive affect words and 10 are negative.

In this study, a PANAS “composite score” was calculated as the total positive score minus the total negative score. 


In the group assigned to the higher intensity of exercise, the PANAS composite affect score predicted:

  1. The improvement in depression severity score
  2. Whether or not a patient’s depression “responded” to the treatment, and
  3. Whether or not the patient achieved remission.

These associations were not found in the group assigned to low dose exercise.

Importantly, it was not simply the positive affect that predicted improvement, but rather the positive affect minus the negative affect. 


Positive affect following the first exercise session can help predict whether or not a particular patient will respond to adjunctive exercise for major depressive disorder. 

Clinical Commentary

It should be noted that when the word “affect” is used here, it actually means the subjective emotional state.

In plain English, this study found that depression was more likely to improve after 12 weeks of exercise in persons who felt good after the first exercise session.

In clinical practice, we could consider augmentation with exercise in persons who report that they feel better when they do exercise. Alternatively, in cases where the affective response to exercise is not clear, we can encourage the person to exercise a few times and see how s/he feels after the exercise.

Given that the predictive value is limited, I suggest that the value of exercise not be ruled out after only one session. Rather, a brief trial of a few sessions should be recommended.

In my clinical experience, it is useful to let the person choose the intensity and type of exercise that makes him feel better. This varies from person to person. 

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Should we add glutamatergic agents in persons with OCD?

Laoutidis et al. Glutamatergic Agents as Add-On Medication for the Treatment of Obsessive-Compulsive Disorder: A Systematic Review and Meta-Analysis. J Clin Psychiatry. 2016 Oct 25. [Epub ahead of print] PubMed PMID: 27780337.


In addition to serotonergic mechanisms, various types of data show that glutamatergic systems are also involved in obsessive-compulsive disorder.

This study was a review and meta-analysis of studies on the use of glutamatergic drugs for the treatment of obsessive-compulsive disorder. 


A detailed search of the literature was done to find relevant double-blind, randomized controlled trials.

The glutamatergic agents included were: acamprosate, riluzole, memantine, N-acetylcysteine, D-cycloserine, lamotrigine, amantadine, and glycine.

Data were extracted independently by 2 reviewers (good). 


Eight relevant double-blind, randomized controlled trials were identified.

The overall response to addition of glutamatergic drugs was statistically significantly greater than with addition of placebo with a risk ratio of 3.7. Note: while the term used is “risk” ratio, it does not have to be an undesirable outcome. Persons who received a glutamatergic drug were 3.7 times more likely to respond than those who received placebo.

Similarly, addition of a glutamatergic drug was efficacious when only “treatment-resistant” patients were considered; risk ratio 4.3.


Addition of a glutamatergic drug was efficacious for persons with obsessive-compulsive disorder, including for “treatment-resistant” illness. 

Clinical Commentary

Given that for most of these drugs, only one randomized controlled trial has been done, addition of one of these drugs is not recommended as a first- or second-line option.

It is interesting to note that the different glutamatergic agents found efficacious for obsessive-compulsive disorder have very different effects on glutamatergic neurotransmission.

Further research into the nature of the glutamatergic dysfunction in obsessive-compulsive disorder is needed along with clinical trials of the efficacy of glutamatergic drugs. 

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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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