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Issue 54, Oct 2016
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Who will progress from mild cognitive impairment to Alzheimer’s disease?

Li et al. Risk factors for predicting progression from mild cognitive impairment to Alzheimer's disease: a systematic review and meta-analysis of cohort studies. J Neurol Neurosurg Psychiatry. 2016 May;87(5):476-84. PubMed PMID: 26001840.


There needs to be a strong focus on prevention or early intervention for Alzheimer’s disease. 

Mild cognitive impairment (MCI) is the transitional stage between the cognitive changes of normal ageing and early dementia.

MCI may or may not progress to Alzheimer’s disease. About 10 to 15% of persons with MCI progress to Alzheimer’s disease each year, which is a high level of risk. 

This study aimed to identify the risk factors for predicting the progression from MCI to Alzheimer's disease.


Six databases were searched for cohort studies on this topic and a meta-analysis of the selected studies was conducted.

Sixty cohort studies with nearly 15,000 participants from 16 countries were included in this meta-analysis. 


The strongest associations with an increased risk of progression from MCI to Alzheimer’s disease were found for:

1. Abnormal CSF phosphorylated tau—relative risk 2.4

2. Abnormal CSF tau/Abeta1-42 ratio—relative risk 3.8

3. Hippocampal atrophy—relative risk 2.6

4. Medial temporal lobe atrophy—relative risk 2.1

5. Entorhinal atrophy—relative risk 2.0

Increased risk was also found with presence of E4E4 form of the apolipoprotein E (APOE) gene (i.e., both genes in the pair are of the E4 form, at least one gene being of the APOE E4 form), CSF total tau, white matter hyperintensity volume, depression, diabetes, hypertension, older age, female gender, lower mini-mental state examination (MMSE) score, and higher Alzheimer’s disease assessment scale cognitive subscale (ADAS-cog) score. 

Decreased risk was associated with high body mass index (relative risk 0.85), and higher auditory verbal learning test delay score (relative risk 0.86). 

No increased risk of progression was found for subcortical infarctions, anxiety, apathy, smoking, cardiovascular disease, cerebrovascular disease, atrial fibrillation, hypercholesterolemia, higher education level, and higher auditory verbal learning test total score. 


Demographic, clinical, neuroimaging, and CSF variables that are associated with the progression of MCI to Alzheimer’s disease were identified. 

Clinical Commentary

In the DSM-5, persons with MCI would be diagnosed as Mild Neurocognitive Disorder. The diagnostic criteria for this disorder include a “modest” reduction in cognitive functioning in one or more areas, e.g., complex attention, executive function, learning and memory, language, perceptual-motor, or social cognition. However, in Mild Neurocognitive Disorder, the cognitive deficits don’t interfere with the ability to do everyday activities independently. 

Since persons with MCI may progress to dementia, remain relatively stable, or even have resolution of the cognitive impairment, understandably, persons with MCI feel an urgent need to get some idea about their prognosis.  

Clinically, an MRI of the brain can be helpful in determining the prognosis. Note that in this paper, the strongest predictors can be identified on an MRI of the brain. 

Risk factors identified in this paper that can potentially be modified include depression, diabetes, and hypertension. It is likely that energetic treatment of these conditions may reduce the risk of dementia in patients with MCI. For example, it has been shown that antihypertensive treatment is protective against progression of MCI (Reitz et al., 2008). These prognostic factors should be widely communicated to patients and family members. Hopefully, they will motivate patients to be diligent in obtaining treatment for depressive disorders, diabetes, and hypertension.

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Does early age at menopause have implications for mental health clinicians?

Georgakis et al. Association of Age at Menopause and Duration of Reproductive Period With Depression After Menopause: A Systematic Review and Meta-analysis. JAMA Psychiatry. 2016 Feb;73(2):139-49. PubMed PMID: 26747373.

Editorial. Joffe H, Bromberger JT. Shifting Paradigms About Hormonal Risk Factors for Postmenopausal Depression: Age at Menopause as an Indicator of Cumulative Lifetime Exposure to Female Reproductive Hormones. JAMA Psychiatry. 2016 Feb;73(2):111-2. doi: 10.1001/jamapsychiatry.2015.2701. PubMed PMID: 26746695.


Estrogens have long been known to be protective against depression and to have neuroprotective effects. 

We know about the increased risk of depression during periods when estrogen levels are changing—in the premenstrual period, postpartum period, and the perimenopause. But what about after menopause has occurred?

The associations between measures of reduced exposure to endogenous estrogens and the risk for postmenopausal depression have not been systematically studied.

This study aimed to look at whether age at menopause and the duration of the reproductive period were associated with the risk for depression among postmenopausal women who had naturally-occurring menopause.


MEDLINE was searched, references of the articles were found, and authors were contacted to identify any other studies. 

Reviewers worked in pairs to identify studies and extract data independently to crosscheck their work. 

Finally, 14 studies were eligible for meta-analysis. 

Among the limitations of the included studies is that the age at menarche and menopause was self-reported retrospectively.

Menopause can be defined operationally as the time 1 year after the last menstrual period. The duration of the reproductive period is then defined as the age at menopause minus the age at menarche. 


The 14 studies included in the meta-analysis represented about 68,000 women.

There was a lower risk of depression with a) increasing age at menopause and b) duration of the reproductive period. 

When age at menopause and duration of the reproductive period were considered in 2-year increments, the odds ratio for depression in both cases was 0.98. (An odds ratio less than 1 means that the risk is decreased.) That is, there was a 2% decrease in risk for every 2-year increase in age at menopause or 2-year increase in duration of the reproductive period. 

When only studies of women with severe depression were looked at, there was a 5% decrease in risk of severe depression with every 2-year increase in age at menopause.

The authors also compared women who had menopause at age 40 or more years to those who had premature menopause (at age less than 40 years). Those who had menopause later had a 50% decreased risk for depression.

Only a few studies controlled statistically for a past history of depression in the participants; in these studies the results were the same as in the overall analysis. 


Shorter exposure to endogenous estrogens, assessed by younger age at menopause and shorter reproductive period, was associated with increased risk of depression after menopause. 

Clinical Commentary

It is important for me to emphasize again that this paper is not about perimenopausal depression, but about postmenopausal depression. Hormonally, the two are very different. 

The editorial accompanying the paper notes that this study suggests a novel idea—that the protective effects of gonadal steroids may extend into the postmenopausal period where levels of estrogen and progesterone are low. 

What are the next steps? Firstly, more rigorously designed studies are needed to confirm, clarify, and expand the findings of this meta-analysis. Secondly, if confirmed, studies will be needed about what interventions could reduce this risk. While we can speculate that treatment with estrogen may be particularly helpful for postmenopausal depression in these patients, at this time it is not recommended that women with postmenopausal depression should routinely be treated with estrogen. 

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Combining a stimulant and guanfacine for treatment of ADHD

McCracken et al. Combined Stimulant and Guanfacine Administration in Attention-Deficit/Hyperactivity Disorder: A Controlled, Comparative Study. J Am Acad Child Adolesc Psychiatry. 2016 Aug;55(8):657-666.e1. PubMed PMID: 27453079; PubMed Central PMCID: PMC4976782.


Pharmacological treatment of attention-deficit/hyperactivity disorder (ADHD) involves improving both dopaminergic and noradrenergic neurotransmission. 

Guanfacine is an alpha 2A agonist and its extended-release formulation is an FDA-approved treatment for ADHD both as monotherapy and as an adjuvant to stimulant medication. 

This study evaluated the efficacy and tolerability of a combination of d-methylphenidate extended-release and guanfacine. 

Addition of guanfacine to a stimulant in patients who had a partial response to a stimulant has been evaluated in the past. This is, however, the first study to compare the combination to monotherapy in children with ADHD who have not failed to show an adequate response to a stimulant. 


This was an 8-week, double-blind, clinical trial in 7- to 14-year-old children with a DSM-IV diagnosis of ADHD. 

The participants were randomized to receive either:

1. Guanfacine 1 to 3 mg/day,

2. D-methylphenidate 5 to 20 mg/day, or 

3. A combination of both medications. 

The efficacy outcome measures were the ADHD Rating Scale IV (ADHD-RS-IV) and the Clinical Global Impression-Improvement (CGI-I) scale. 

The proportions of patients much or very much improved after treatment were about 70% with guanfacine alone, about 80% with d-methylphenidate alone, and about 90% with the combination. The 10% difference between d-methylphenidate and the combination just meets the commonly accepted minimum difference in response rate that is considered clinically significant. 


A total of 207 participants were randomized and received drug. 

All three of the treatment groups showed statistically significant improvement in the total score on the ADHD-RS-IV scale as well as on inattentive symptoms specifically. 

The combination medication group had a greater reduction in ADHD-RS-IV Inattentive subscale scores and the CGI-I scores. 

No serious cardiovascular events occurred. 

Sedation, somnolence, lethargy, and fatigue were greater in both the guanfacine monotherapy and the combination treatment groups. 


The combination of d-methylphenidate and guanfacine showed greater improvement in ADHD symptoms but with an increase in sedation/fatigue type symptoms. 

Clinical Commentary

As in many other clinical situations, combining medications can lead to greater improvement than use of either medication alone. 

D-methylphenidate, used in this study, is available in the US under the brand name Focalin. However, there is no reason to think that the benefit of using guanfacine along with a stimulant is limited to d-methylphenidate. Guanfacine could also be used in combination with other stimulants when clinically appropriate. As previously noted in GME Research Review (, guanfacine extended-release is used along with lisdexamfetamine is one of the combinations used by many patients in the US. 

Since the guanfacine is often associated with sedation/somnolence, this is sometimes used to advantage in patients with ADHD who need adjunctive medication and are also very anxious or have insomnia. 

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Why is the prevalence of major depression not changing?

Patten SB, Williams JV, Lavorato DH, Bulloch AG, Wiens K, Wang J. Why is major depression prevalence not changing? J Affect Disord. 2016 Jan 15;190:93-7. PubMed PMID: 26485311.


With greater provision of treatment one would expect a decreased burden of major depressive episodes (MDE) in the general population. However, there is no evidence yet that this has happened. 

Studies in the US, Canada, UK, and Australia have all shown that despite availability of antidepressants that are better tolerated and a massive increase in prescribing of antidepressants, the prevalence of MDE has not decreased. 

This is puzzling! What could be potential reasons for this? 

1. Treatment may not be effective enough to make a difference at the population level

2. The benefits of treatment such as decreased episode duration may be offset by other trends such as increasing episode incidence, or vice versa.

The goal of this study was to determine whether there is any evidence of:

1. Decreasing mean duration of MDE in the population over time

2. Increasing incidence of MDE that may be offsetting the decreased mean duration of the episodes. 


This analysis used the prevalence of MDE as assessed by a series of national surveys and in a nation-wide longitudinal study in Canada. 

These studies included the same instrument—a short-form version of the Composite International Diagnostic Interview module for major depression. 

Indicators of the incidence and episode duration of MDE were estimated and trends over time were assessed.


There was no evidence of diminishing duration of MDE or of increasing incidence of MDE. 

The overall mean duration of the episodes was 14.0 weeks and did not change significantly over time. 

The estimated incidence of new episodes was 1.8% per year and, again, did not change significantly over time. 


These results suggest that at a population level currently delivered treatments do not effectively reduce the burden of MDE in the population by either substantially reducing the duration of episodes or preventing future episodes. 

Clinical Commentary

We would love to hear from you about what you think are the reasons that the burden of MDE’s has not decreased. Email me at [email protected]

In my opinion, one of the important reasons is that the great majority of patients who should get long-term prophylactic (maintenance) antidepressants do not get them. This is a huge problem that needs to be urgently addressed by us by educating both patients and prescribing clinicians about the importance of maintenance treatment in recurrent major depressive disorder.  

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What kind of childhood abuse is associated with risk of depressive disorders?

Infurna et al. Associations between depression and specific childhood experiences of abuse and neglect: A meta-analysis. J Affect Disord. 2016 Jan 15;190:47-55. PubMed PMID: 26480211.


There is a strong relationship between childhood abuse and subsequent development of clinical depression. 

However, there has been only limited research into the association between various types of childhood abuse/neglect and risk of developing clinical depression. 

More attention has been paid in the past to physical and sexual abuse as risk factors for the development of major depression. 

This meta-analysis estimated the associations between depression and different types of childhood maltreatment:

1. Antipathy (parental criticism and hostility, coldness or rejection shown toward the child, including scapegoating the child in contrast to treatment of siblings)

2. Neglect (failure to provide for the child's basic material needs like food, clothing, shelter, and protection, or for developmental needs like interest in school, friends, child's happiness, health, and well-being).

3. Psychological abuse (includes humiliation, terrorization, or intentional deprivation of needs or valued objects usually in the context of a parental, highly controlling and domineering relationship with the child).

4. Physical abuse (Violence directed towards the child by a household member including hitting about the head or being hit hard around the body with the hands/fists, being hit with an implement, kicked, bitten, or burned, or threats or use of a gun or knife).

5. Sexual abuse (including intercourse, violation or penetration with an object, oral sex, touching of breasts/genitals, requiring the child to watch sexual activity or pornography, verbal solicitations for sex, age-inappropriate verbal content).


A systematic search of the literature was done for studies that used the Childhood Experience of Care and Abuse (CECA) interview and strict clinical assessment for major depression. 


The meta-analysis included 12 primary studies with a total of about 4400 participants.

The effect sizes for the association with subsequent development of depression were as follows: 

Neglect 0.9 (large effect)

Psychological abuse 0.9 (large effect)

Physical abuse 0.8 (large effect)

Antipathy 0.5 (moderate effect)

Sexual abuse 0.5 (moderate effect)

Overall, childhood maltreatment was more strongly associated with depression in adolescents than in adults. 


This meta-analysis found that neglect, psychological abuse, and physical abuse were most strongly associated with development of major depression. 

Sexual abuse, although statistically significant, was less strongly related. 

Thus, we must remember that in addition to physical and sexual abuse, the more "silent" types of childhood maltreatment also have a strong impact on the development of major depression.

Further clarification is needed as to which types of maltreatment exert their worst effects at what ages. 

Clinical Commentary

In clinical work, we should ask not only about childhood physical or sexual abuse but about psychological abuse or neglect as well. 

An interesting question is whether the patient’s report of what happened is accurate. Thus, as clinicians, I think we should always think of what the patient’s report as the patient’s “narrative” rather than an objective description of the events. But the narrative is very important psychologically!

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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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