Fatigue and depression can be viewed as a “vicious cycle”: Fatigue can be a symptom of major depression, and fatigue can be a risk factor for depression.¹ For example, fatigue associated with a general medical condition or traumatic brain injury can be a risk factor for developing major depressive disorder (MDD).^1-3 It isn’t surprising that fatigue has been studied as a predictor of relapse after previous response to treatment in patients with MDD.

Despite the observed association between fatigue and depression, their underlying relationship often is unclear. The literature does not differentiate among fatigue associated with depression, fatigue as a treatment-emergent adverse effect, and fatigue as a residual symptom of depression that is partially responsive to treatment.^4,5 To complicate the situation, many medications used to treat MDD can cause fatigue.

Patients often describe fatigue as (1) feeling tired, exhausted, or drained and (2) lacking energy and motivation. Fatigue can be related to impaired wakefulness but is believed to be a different entity than sleepiness.⁶ Residual fatigue can affect social, cognitive, emotional, and physical health.

We reviewed the literature about fatigue as a symptom of MDD by conducting a search of Medline, PubMed, and Google Scholar, using keywords depression, fatigue, residual symptoms, and treatment. We chose the papers cited in this article based on our consensus and because these publications represent expert opinion or the highest quality evi­dence available.

Residual fatigue has an effect on prognosis
Fatigue is a common symptom of MDD that persists in 20% to 30% of patients whose symptoms of depression otherwise remit.^4,7-9 Several studies have linked residual fatigue with the overall prognosis of MDD.⁵ Data from a prospective study demonstrate that depressed patients have a higher risk of relapse when they continue to report symp­toms of fatigue after their symptoms of depression have otherwise entered partial remission.¹⁰ Another study demonstrated that the severity of residual symptoms of depression is a strong predictor of another major depressive episode.¹¹

In a large-scale study, the prevalence of residual fatigue after adequate treat­ment of MDD in both partial responders and remitters was 84.6%.¹² The same study showed that one-third of patients who had been treated for MDD had persistent and clinically significant fatigue, which could suggest a relationship between fatigue and selective serotonin reuptake inhibitors (SSRIs) and other antidepressants.

Another study demonstrated that 64.6% of patients who responded to antidepressant treatment and who had baseline fatigue con­tinued to exhibit symptoms of fatigue after an adequate trial of an antidepressant.¹³

Neurobiological considerations
Studies have shown that the neuronal circuits that malfunction in fatigue are different from those that malfunction in depression.¹⁴ Although the neurobiol­ogy of fatigue has not been determined, decreased neuronal activity in the prefron­tal circuits has been associated with symp­toms of fatigue.¹⁵

In addition, evidence from the litera­ture shows a decrease in hormone secre­tion¹⁶ and cognitive abilities in patients exhibiting symptoms of fatigue.¹⁷ These findings have led some experts to hypoth­esize that symptoms of fatigue associated with depression could be the result of (1) immune dysregulation¹⁸ and (2) an inability of available antidepressants to tar­get the underlying biology of the disorder.²

Despite the hypothesis that fatigue asso­ciated with depression might be biologically related to immune dysregulation, some authors continue to point to an imbalance in neurotransmitters—norepinephrine, his­tamine, dopamine, acetylcholine—as being  associated with fatigue.¹⁴ For example, a study demonstrated that drugs targeting noradrenergic reuptake inhibition were more effective at preventing a relapse of fatigue compared with serotonergic drugs.¹⁹ Another study showed improvement in energy with an increase in the plasma level of desipramine, which affects noradrener­gic neurotransmission.²⁰

Inflammatory cytokines also have been explored in the search for an understand­ing of the etiology of fatigue and depres­sion.²¹ Physical and mental stress promote the release of cytokines, which activate the immune system by inducing an inflam­matory response; this response has been etiologically linked to depressive disor­ders.²² Furthermore, studies have demon­strated an elevated level of inflammatory cytokines in patients who have MDD— suggesting that MDD is associated with a chronic low level of inflammation that crosses the blood−brain barrier.²³

Clinical considerations: A role for rating scales?
Despite the significance of residual fatigue on the quality of life of patients who have MDD, most common rating scales, such as the Hamilton Depression Rating Scale²⁴ and the Montgomery-Åsberg Depression Rating Scale,²⁵ have limited sensitivity for measuring fatigue.²⁶ The Fatigue Associated with Depression (FAsD)²⁷ questionnaire, designed according to FDA guidelines,²⁸ is used to assess fatigue associated with depression. The final version of the FAsD includes 13 items: a 6-item experience sub­scale and a 7-item impact subscale.

Is the FAsD helpful? The experience sub­scale of the FAsD assesses how often the patient experiences different aspects of fatigue (tiredness, exhaustion, lack of energy, physical weakness, and a feeling that everything requires too much effort). The impact subscale of the FAsD assesses the effect of fatigue on daily life.

The overall FAsD score is calculated by taking the mean of each subscale; a change of 0.67 on the experience subscale and 0.57 on the impact subscale are considered clini­cally meaningful.²⁷ The measurement prop­erties of the questionnaire showed internal consistency, reliability, and validity in test­ing. Researchers note, however, that FAsD does not include items to assess the impact of fatigue on cognition. This means that the FAsD might not distinguish between physi­cal and mental aspects of fatigue.

Treatment
It isn’t surprising that residual depres­sion can increase health care utilization and economic burden, including such indirect costs as lost productivity and wages.²⁹ Despite these impacts, there is a paucity of studies evaluating the relation­ship between residual symptoms, such as fatigue, and work productivity. It has been established that improving a depressed patient’s level of energy correlates with improved performance at work.

Treating fatigue as a residual symp­tom of MDD can be complicated because symptoms of fatigue might be:
   • a discrete symptom of MDD
   • a prodromal symptom of another disorder
   • an adverse effect of an antidepressant.^2,30

It is a major clinical problem, there­fore, that antidepressants can alleviate and cause symptoms of fatigue.³¹ Treatment strategy should focus on identifying anti­depressants that are less likely to cause fatigue (ie, noradrenergic or dopaminergic drugs, or both). Adjunctive treatments to target residual fatigue also can be used.³²

There are limited published data on the effective treatment of residual fatigue in patients with MDD. Given the absence of sufficient evidence, agents that promote noradrenergic and dopaminergic neuro­transmission have been the treatment of choice when targeting fatigue in depressed patients.^2,14,21,33

The Table^34-37 lists poten­tial treatment options often used to treat fatigue associated with depression.

SSRIs. Treatment with SSRIs has been asso­ciated with a low probability of achiev­ing remission when targeting fatigue as a symptom of MDD.²¹

One study reported that, after 8 weeks of treatment with an SSRI, treatment-emergent adverse events, such as worsening fatigue and weakness, were observed—along with an overall lack of efficacy in targeting all symptoms of depression.³⁸

Another study demonstrated positive effects when a noradrenergic agent was added to an SSRI in partial responders who continued to complain of residual fatigue.³³

However, studies that compared the effects of SSRIs with those of antidepres­sants that have pronoradrenergic effects showed that the 2 mechanisms of action were not significantly different from each other in their ability to resolve residual symptoms of fatigue.²¹ A limiting factor might be that these studies were retrospec­tive and did not analyze the efficacy of a noradrenergic agent as an adjunct for alle­viating symptoms of fatigue.³⁹

Bupropion. This commonly used medica­tion for fatigue is believed to cause a sig­nificantly lower level of fatigue compared with SSRIs.⁴⁰ The potential utility of bupro­pion in this area could be a reflection of its mechanism of action—ie, the drug targets both noradrenergic and dopaminergic neurotransmission.⁴¹

A study comparing bupropion with SSRIs in targeting somatic symptoms of depression reported a small but statisti­cally significant difference in favor of the bupropion-treated group. However, this finding was confounded by the small effect size and difficulty quantifying somatic symptoms.⁴⁰

Stimulants and modafinil. Psycho-stimulants have been shown to be effica­cious for depression and fatigue, both as monotherapy and adjunctively.^39,42

Modafinil has demonstrated efficacy in open-label trials for improving residual fatigue, but failed to separate from pla­cebo in controlled trials.⁴³ At least 1 other failed study has been published examining modafinil as a treatment for fatigue associ­ated with depression.⁴³

Adjunctive therapy with CNS stimu­lants, such as amphetamine/dextroam­phetamine and methylphenidate, has been used to treat fatigue, with positive results.¹⁶ Modafinil and stimulants also could be tried as an augmentation strategy to other antidepressants; such use is off-label and should be attempted only after careful consideration.¹⁶

Exercise might be a nonpharmacothera­peutic modality that targets the underly­ing physiology associated with fatigue. Exercise releases endorphins, which can affect overall brain chemistry and which have been theorized to diminish symp­toms of fatigue and depression.⁴⁴ Consider exercise in addition to treatment with an antidepressant in selected patients.⁴⁵

To sum up
In general, the literature does not recom­mend one medication as superior to any other for treating fatigue that is a residual symptom of depression. Such hesitation suggests that more empirical studies are needed to determine what is the best and proper management of treating fatigue associated with depression.

Bottom LinE
Fatigue can be a symptom of major depressive disorder (MDD) or a risk factor for depression. Fatigue has been studied as a predictor of relapse after previous response to treatment in patients with MDD. Residual fatigue can affect social, cognitive, emotional, and physical health and can result in increased utilization of health care services. A number of treatment options are available; none has been shown to be superior to the others.

Related Resources
• Leone SS. A disabling combination: fatigue and depression. Br J Psychiatry. 2010;197(2):86-87.
• Targum SD, Fava M. Fatigue as a residual symptom of de­pression. Innov Clin Neurosci. 2011;8(10):40-43.
• Illiades C. How to fight depression fatigue. Everyday Health. http://www.everydayhealth.com/health-report/major-depression-living-well/fight-depression-fatigue.aspx.
• Kerr M. Depression and fatigue: a vicious cycle. Healthline. http://www.healthline.com/health/depression/fatigue.

Drug Brand Names
Amphetamine/dextroamphetamine • Adderall              
Bupropion • Wellbutrin                                                
Desipramine • Norpramin                                           
Methylphenidate • Ritalin
Modafinil • Provigil
Sertraline • Zoloft
Venlafaxine • Effexor

Disclosures
Dr. Sohail reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Macaluso has conducted clinical trials research as principal investigator for the following pharmaceutical manufacturers in the past 12 months: AbbVie, Inc.; Alkermes; AssureRx Health, Inc.; Eisai Co., Ltd.; FORUM Pharmaceuticals, Inc.; Janssen Pharmaceuticals, Inc.; and Naurex Inc. All clinical trial and study contracts were with, and payments were made to, University of Kansas Medical Center Research Institute, Kansas City, Kansas, a research institute affiliated with University of Kansas School of Medicine−Wichita.

Fatigue and depression can be viewed as a “vicious cycle”: Fatigue can be a symptom of major depression, and fatigue can be a risk factor for depression.¹ For example, fatigue associated with a general medical condition or traumatic brain injury can be a risk factor for developing major depressive disorder (MDD).^1-3 It isn’t surprising that fatigue has been studied as a predictor of relapse after previous response to treatment in patients with MDD.

Despite the observed association between fatigue and depression, their underlying relationship often is unclear. The literature does not differentiate among fatigue associated with depression, fatigue as a treatment-emergent adverse effect, and fatigue as a residual symptom of depression that is partially responsive to treatment.^4,5 To complicate the situation, many medications used to treat MDD can cause fatigue.

Patients often describe fatigue as (1) feeling tired, exhausted, or drained and (2) lacking energy and motivation. Fatigue can be related to impaired wakefulness but is believed to be a different entity than sleepiness.⁶ Residual fatigue can affect social, cognitive, emotional, and physical health.

We reviewed the literature about fatigue as a symptom of MDD by conducting a search of Medline, PubMed, and Google Scholar, using keywords depression, fatigue, residual symptoms, and treatment. We chose the papers cited in this article based on our consensus and because these publications represent expert opinion or the highest quality evi­dence available.

Residual fatigue has an effect on prognosis
Fatigue is a common symptom of MDD that persists in 20% to 30% of patients whose symptoms of depression otherwise remit.^4,7-9 Several studies have linked residual fatigue with the overall prognosis of MDD.⁵ Data from a prospective study demonstrate that depressed patients have a higher risk of relapse when they continue to report symp­toms of fatigue after their symptoms of depression have otherwise entered partial remission.¹⁰ Another study demonstrated that the severity of residual symptoms of depression is a strong predictor of another major depressive episode.¹¹

In a large-scale study, the prevalence of residual fatigue after adequate treat­ment of MDD in both partial responders and remitters was 84.6%.¹² The same study showed that one-third of patients who had been treated for MDD had persistent and clinically significant fatigue, which could suggest a relationship between fatigue and selective serotonin reuptake inhibitors (SSRIs) and other antidepressants.

Another study demonstrated that 64.6% of patients who responded to antidepressant treatment and who had baseline fatigue con­tinued to exhibit symptoms of fatigue after an adequate trial of an antidepressant.¹³

Neurobiological considerations
Studies have shown that the neuronal circuits that malfunction in fatigue are different from those that malfunction in depression.¹⁴ Although the neurobiol­ogy of fatigue has not been determined, decreased neuronal activity in the prefron­tal circuits has been associated with symp­toms of fatigue.¹⁵

In addition, evidence from the litera­ture shows a decrease in hormone secre­tion¹⁶ and cognitive abilities in patients exhibiting symptoms of fatigue.¹⁷ These findings have led some experts to hypoth­esize that symptoms of fatigue associated with depression could be the result of (1) immune dysregulation¹⁸ and (2) an inability of available antidepressants to tar­get the underlying biology of the disorder.²

Despite the hypothesis that fatigue asso­ciated with depression might be biologically related to immune dysregulation, some authors continue to point to an imbalance in neurotransmitters—norepinephrine, his­tamine, dopamine, acetylcholine—as being  associated with fatigue.¹⁴ For example, a study demonstrated that drugs targeting noradrenergic reuptake inhibition were more effective at preventing a relapse of fatigue compared with serotonergic drugs.¹⁹ Another study showed improvement in energy with an increase in the plasma level of desipramine, which affects noradrener­gic neurotransmission.²⁰

Inflammatory cytokines also have been explored in the search for an understand­ing of the etiology of fatigue and depres­sion.²¹ Physical and mental stress promote the release of cytokines, which activate the immune system by inducing an inflam­matory response; this response has been etiologically linked to depressive disor­ders.²² Furthermore, studies have demon­strated an elevated level of inflammatory cytokines in patients who have MDD— suggesting that MDD is associated with a chronic low level of inflammation that crosses the blood−brain barrier.²³

Clinical considerations: A role for rating scales?
Despite the significance of residual fatigue on the quality of life of patients who have MDD, most common rating scales, such as the Hamilton Depression Rating Scale²⁴ and the Montgomery-Åsberg Depression Rating Scale,²⁵ have limited sensitivity for measuring fatigue.²⁶ The Fatigue Associated with Depression (FAsD)²⁷ questionnaire, designed according to FDA guidelines,²⁸ is used to assess fatigue associated with depression. The final version of the FAsD includes 13 items: a 6-item experience sub­scale and a 7-item impact subscale.

Is the FAsD helpful? The experience sub­scale of the FAsD assesses how often the patient experiences different aspects of fatigue (tiredness, exhaustion, lack of energy, physical weakness, and a feeling that everything requires too much effort). The impact subscale of the FAsD assesses the effect of fatigue on daily life.

The overall FAsD score is calculated by taking the mean of each subscale; a change of 0.67 on the experience subscale and 0.57 on the impact subscale are considered clini­cally meaningful.²⁷ The measurement prop­erties of the questionnaire showed internal consistency, reliability, and validity in test­ing. Researchers note, however, that FAsD does not include items to assess the impact of fatigue on cognition. This means that the FAsD might not distinguish between physi­cal and mental aspects of fatigue.

Treatment
It isn’t surprising that residual depres­sion can increase health care utilization and economic burden, including such indirect costs as lost productivity and wages.²⁹ Despite these impacts, there is a paucity of studies evaluating the relation­ship between residual symptoms, such as fatigue, and work productivity. It has been established that improving a depressed patient’s level of energy correlates with improved performance at work.

Treating fatigue as a residual symp­tom of MDD can be complicated because symptoms of fatigue might be:
   • a discrete symptom of MDD
   • a prodromal symptom of another disorder
   • an adverse effect of an antidepressant.^2,30

It is a major clinical problem, there­fore, that antidepressants can alleviate and cause symptoms of fatigue.³¹ Treatment strategy should focus on identifying anti­depressants that are less likely to cause fatigue (ie, noradrenergic or dopaminergic drugs, or both). Adjunctive treatments to target residual fatigue also can be used.³²

There are limited published data on the effective treatment of residual fatigue in patients with MDD. Given the absence of sufficient evidence, agents that promote noradrenergic and dopaminergic neuro­transmission have been the treatment of choice when targeting fatigue in depressed patients.^2,14,21,33

The Table^34-37 lists poten­tial treatment options often used to treat fatigue associated with depression.

SSRIs. Treatment with SSRIs has been asso­ciated with a low probability of achiev­ing remission when targeting fatigue as a symptom of MDD.²¹

One study reported that, after 8 weeks of treatment with an SSRI, treatment-emergent adverse events, such as worsening fatigue and weakness, were observed—along with an overall lack of efficacy in targeting all symptoms of depression.³⁸

Another study demonstrated positive effects when a noradrenergic agent was added to an SSRI in partial responders who continued to complain of residual fatigue.³³

However, studies that compared the effects of SSRIs with those of antidepres­sants that have pronoradrenergic effects showed that the 2 mechanisms of action were not significantly different from each other in their ability to resolve residual symptoms of fatigue.²¹ A limiting factor might be that these studies were retrospec­tive and did not analyze the efficacy of a noradrenergic agent as an adjunct for alle­viating symptoms of fatigue.³⁹

Bupropion. This commonly used medica­tion for fatigue is believed to cause a sig­nificantly lower level of fatigue compared with SSRIs.⁴⁰ The potential utility of bupro­pion in this area could be a reflection of its mechanism of action—ie, the drug targets both noradrenergic and dopaminergic neurotransmission.⁴¹

A study comparing bupropion with SSRIs in targeting somatic symptoms of depression reported a small but statisti­cally significant difference in favor of the bupropion-treated group. However, this finding was confounded by the small effect size and difficulty quantifying somatic symptoms.⁴⁰

Stimulants and modafinil. Psycho-stimulants have been shown to be effica­cious for depression and fatigue, both as monotherapy and adjunctively.^39,42

Modafinil has demonstrated efficacy in open-label trials for improving residual fatigue, but failed to separate from pla­cebo in controlled trials.⁴³ At least 1 other failed study has been published examining modafinil as a treatment for fatigue associ­ated with depression.⁴³

Adjunctive therapy with CNS stimu­lants, such as amphetamine/dextroam­phetamine and methylphenidate, has been used to treat fatigue, with positive results.¹⁶ Modafinil and stimulants also could be tried as an augmentation strategy to other antidepressants; such use is off-label and should be attempted only after careful consideration.¹⁶

Exercise might be a nonpharmacothera­peutic modality that targets the underly­ing physiology associated with fatigue. Exercise releases endorphins, which can affect overall brain chemistry and which have been theorized to diminish symp­toms of fatigue and depression.⁴⁴ Consider exercise in addition to treatment with an antidepressant in selected patients.⁴⁵

To sum up
In general, the literature does not recom­mend one medication as superior to any other for treating fatigue that is a residual symptom of depression. Such hesitation suggests that more empirical studies are needed to determine what is the best and proper management of treating fatigue associated with depression.

Bottom LinE
Fatigue can be a symptom of major depressive disorder (MDD) or a risk factor for depression. Fatigue has been studied as a predictor of relapse after previous response to treatment in patients with MDD. Residual fatigue can affect social, cognitive, emotional, and physical health and can result in increased utilization of health care services. A number of treatment options are available; none has been shown to be superior to the others.

Related Resources
• Leone SS. A disabling combination: fatigue and depression. Br J Psychiatry. 2010;197(2):86-87.
• Targum SD, Fava M. Fatigue as a residual symptom of de­pression. Innov Clin Neurosci. 2011;8(10):40-43.
• Illiades C. How to fight depression fatigue. Everyday Health. http://www.everydayhealth.com/health-report/major-depression-living-well/fight-depression-fatigue.aspx.
• Kerr M. Depression and fatigue: a vicious cycle. Healthline. http://www.healthline.com/health/depression/fatigue.

Drug Brand Names
Amphetamine/dextroamphetamine • Adderall              
Bupropion • Wellbutrin                                                
Desipramine • Norpramin                                           
Methylphenidate • Ritalin
Modafinil • Provigil
Sertraline • Zoloft
Venlafaxine • Effexor

Disclosures
Dr. Sohail reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Macaluso has conducted clinical trials research as principal investigator for the following pharmaceutical manufacturers in the past 12 months: AbbVie, Inc.; Alkermes; AssureRx Health, Inc.; Eisai Co., Ltd.; FORUM Pharmaceuticals, Inc.; Janssen Pharmaceuticals, Inc.; and Naurex Inc. All clinical trial and study contracts were with, and payments were made to, University of Kansas Medical Center Research Institute, Kansas City, Kansas, a research institute affiliated with University of Kansas School of Medicine−Wichita.

Fatigue and depression can be viewed as a “vicious cycle”: Fatigue can be a symptom of major depression, and fatigue can be a risk factor for depression.¹ For example, fatigue associated with a general medical condition or traumatic brain injury can be a risk factor for developing major depressive disorder (MDD).^1-3 It isn’t surprising that fatigue has been studied as a predictor of relapse after previous response to treatment in patients with MDD.

Despite the observed association between fatigue and depression, their underlying relationship often is unclear. The literature does not differentiate among fatigue associated with depression, fatigue as a treatment-emergent adverse effect, and fatigue as a residual symptom of depression that is partially responsive to treatment.^4,5 To complicate the situation, many medications used to treat MDD can cause fatigue.

Patients often describe fatigue as (1) feeling tired, exhausted, or drained and (2) lacking energy and motivation. Fatigue can be related to impaired wakefulness but is believed to be a different entity than sleepiness.⁶ Residual fatigue can affect social, cognitive, emotional, and physical health.

We reviewed the literature about fatigue as a symptom of MDD by conducting a search of Medline, PubMed, and Google Scholar, using keywords depression, fatigue, residual symptoms, and treatment. We chose the papers cited in this article based on our consensus and because these publications represent expert opinion or the highest quality evi­dence available.

Residual fatigue has an effect on prognosis
Fatigue is a common symptom of MDD that persists in 20% to 30% of patients whose symptoms of depression otherwise remit.^4,7-9 Several studies have linked residual fatigue with the overall prognosis of MDD.⁵ Data from a prospective study demonstrate that depressed patients have a higher risk of relapse when they continue to report symp­toms of fatigue after their symptoms of depression have otherwise entered partial remission.¹⁰ Another study demonstrated that the severity of residual symptoms of depression is a strong predictor of another major depressive episode.¹¹

In a large-scale study, the prevalence of residual fatigue after adequate treat­ment of MDD in both partial responders and remitters was 84.6%.¹² The same study showed that one-third of patients who had been treated for MDD had persistent and clinically significant fatigue, which could suggest a relationship between fatigue and selective serotonin reuptake inhibitors (SSRIs) and other antidepressants.

Another study demonstrated that 64.6% of patients who responded to antidepressant treatment and who had baseline fatigue con­tinued to exhibit symptoms of fatigue after an adequate trial of an antidepressant.¹³

Neurobiological considerations
Studies have shown that the neuronal circuits that malfunction in fatigue are different from those that malfunction in depression.¹⁴ Although the neurobiol­ogy of fatigue has not been determined, decreased neuronal activity in the prefron­tal circuits has been associated with symp­toms of fatigue.¹⁵

In addition, evidence from the litera­ture shows a decrease in hormone secre­tion¹⁶ and cognitive abilities in patients exhibiting symptoms of fatigue.¹⁷ These findings have led some experts to hypoth­esize that symptoms of fatigue associated with depression could be the result of (1) immune dysregulation¹⁸ and (2) an inability of available antidepressants to tar­get the underlying biology of the disorder.²

Despite the hypothesis that fatigue asso­ciated with depression might be biologically related to immune dysregulation, some authors continue to point to an imbalance in neurotransmitters—norepinephrine, his­tamine, dopamine, acetylcholine—as being  associated with fatigue.¹⁴ For example, a study demonstrated that drugs targeting noradrenergic reuptake inhibition were more effective at preventing a relapse of fatigue compared with serotonergic drugs.¹⁹ Another study showed improvement in energy with an increase in the plasma level of desipramine, which affects noradrener­gic neurotransmission.²⁰

Inflammatory cytokines also have been explored in the search for an understand­ing of the etiology of fatigue and depres­sion.²¹ Physical and mental stress promote the release of cytokines, which activate the immune system by inducing an inflam­matory response; this response has been etiologically linked to depressive disor­ders.²² Furthermore, studies have demon­strated an elevated level of inflammatory cytokines in patients who have MDD— suggesting that MDD is associated with a chronic low level of inflammation that crosses the blood−brain barrier.²³

Clinical considerations: A role for rating scales?
Despite the significance of residual fatigue on the quality of life of patients who have MDD, most common rating scales, such as the Hamilton Depression Rating Scale²⁴ and the Montgomery-Åsberg Depression Rating Scale,²⁵ have limited sensitivity for measuring fatigue.²⁶ The Fatigue Associated with Depression (FAsD)²⁷ questionnaire, designed according to FDA guidelines,²⁸ is used to assess fatigue associated with depression. The final version of the FAsD includes 13 items: a 6-item experience sub­scale and a 7-item impact subscale.

Is the FAsD helpful? The experience sub­scale of the FAsD assesses how often the patient experiences different aspects of fatigue (tiredness, exhaustion, lack of energy, physical weakness, and a feeling that everything requires too much effort). The impact subscale of the FAsD assesses the effect of fatigue on daily life.

The overall FAsD score is calculated by taking the mean of each subscale; a change of 0.67 on the experience subscale and 0.57 on the impact subscale are considered clini­cally meaningful.²⁷ The measurement prop­erties of the questionnaire showed internal consistency, reliability, and validity in test­ing. Researchers note, however, that FAsD does not include items to assess the impact of fatigue on cognition. This means that the FAsD might not distinguish between physi­cal and mental aspects of fatigue.

Treatment
It isn’t surprising that residual depres­sion can increase health care utilization and economic burden, including such indirect costs as lost productivity and wages.²⁹ Despite these impacts, there is a paucity of studies evaluating the relation­ship between residual symptoms, such as fatigue, and work productivity. It has been established that improving a depressed patient’s level of energy correlates with improved performance at work.

Treating fatigue as a residual symp­tom of MDD can be complicated because symptoms of fatigue might be:
   • a discrete symptom of MDD
   • a prodromal symptom of another disorder
   • an adverse effect of an antidepressant.^2,30

It is a major clinical problem, there­fore, that antidepressants can alleviate and cause symptoms of fatigue.³¹ Treatment strategy should focus on identifying anti­depressants that are less likely to cause fatigue (ie, noradrenergic or dopaminergic drugs, or both). Adjunctive treatments to target residual fatigue also can be used.³²

There are limited published data on the effective treatment of residual fatigue in patients with MDD. Given the absence of sufficient evidence, agents that promote noradrenergic and dopaminergic neuro­transmission have been the treatment of choice when targeting fatigue in depressed patients.^2,14,21,33

The Table^34-37 lists poten­tial treatment options often used to treat fatigue associated with depression.

SSRIs. Treatment with SSRIs has been asso­ciated with a low probability of achiev­ing remission when targeting fatigue as a symptom of MDD.²¹

One study reported that, after 8 weeks of treatment with an SSRI, treatment-emergent adverse events, such as worsening fatigue and weakness, were observed—along with an overall lack of efficacy in targeting all symptoms of depression.³⁸

Another study demonstrated positive effects when a noradrenergic agent was added to an SSRI in partial responders who continued to complain of residual fatigue.³³

However, studies that compared the effects of SSRIs with those of antidepres­sants that have pronoradrenergic effects showed that the 2 mechanisms of action were not significantly different from each other in their ability to resolve residual symptoms of fatigue.²¹ A limiting factor might be that these studies were retrospec­tive and did not analyze the efficacy of a noradrenergic agent as an adjunct for alle­viating symptoms of fatigue.³⁹

Bupropion. This commonly used medica­tion for fatigue is believed to cause a sig­nificantly lower level of fatigue compared with SSRIs.⁴⁰ The potential utility of bupro­pion in this area could be a reflection of its mechanism of action—ie, the drug targets both noradrenergic and dopaminergic neurotransmission.⁴¹

A study comparing bupropion with SSRIs in targeting somatic symptoms of depression reported a small but statisti­cally significant difference in favor of the bupropion-treated group. However, this finding was confounded by the small effect size and difficulty quantifying somatic symptoms.⁴⁰

Stimulants and modafinil. Psycho-stimulants have been shown to be effica­cious for depression and fatigue, both as monotherapy and adjunctively.^39,42

Modafinil has demonstrated efficacy in open-label trials for improving residual fatigue, but failed to separate from pla­cebo in controlled trials.⁴³ At least 1 other failed study has been published examining modafinil as a treatment for fatigue associ­ated with depression.⁴³

Adjunctive therapy with CNS stimu­lants, such as amphetamine/dextroam­phetamine and methylphenidate, has been used to treat fatigue, with positive results.¹⁶ Modafinil and stimulants also could be tried as an augmentation strategy to other antidepressants; such use is off-label and should be attempted only after careful consideration.¹⁶

Exercise might be a nonpharmacothera­peutic modality that targets the underly­ing physiology associated with fatigue. Exercise releases endorphins, which can affect overall brain chemistry and which have been theorized to diminish symp­toms of fatigue and depression.⁴⁴ Consider exercise in addition to treatment with an antidepressant in selected patients.⁴⁵

To sum up
In general, the literature does not recom­mend one medication as superior to any other for treating fatigue that is a residual symptom of depression. Such hesitation suggests that more empirical studies are needed to determine what is the best and proper management of treating fatigue associated with depression.

Bottom LinE
Fatigue can be a symptom of major depressive disorder (MDD) or a risk factor for depression. Fatigue has been studied as a predictor of relapse after previous response to treatment in patients with MDD. Residual fatigue can affect social, cognitive, emotional, and physical health and can result in increased utilization of health care services. A number of treatment options are available; none has been shown to be superior to the others.

Related Resources
• Leone SS. A disabling combination: fatigue and depression. Br J Psychiatry. 2010;197(2):86-87.
• Targum SD, Fava M. Fatigue as a residual symptom of de­pression. Innov Clin Neurosci. 2011;8(10):40-43.
• Illiades C. How to fight depression fatigue. Everyday Health. http://www.everydayhealth.com/health-report/major-depression-living-well/fight-depression-fatigue.aspx.
• Kerr M. Depression and fatigue: a vicious cycle. Healthline. http://www.healthline.com/health/depression/fatigue.

Drug Brand Names
Amphetamine/dextroamphetamine • Adderall              
Bupropion • Wellbutrin                                                
Desipramine • Norpramin                                           
Methylphenidate • Ritalin
Modafinil • Provigil
Sertraline • Zoloft
Venlafaxine • Effexor

Disclosures
Dr. Sohail reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Macaluso has conducted clinical trials research as principal investigator for the following pharmaceutical manufacturers in the past 12 months: AbbVie, Inc.; Alkermes; AssureRx Health, Inc.; Eisai Co., Ltd.; FORUM Pharmaceuticals, Inc.; Janssen Pharmaceuticals, Inc.; and Naurex Inc. All clinical trial and study contracts were with, and payments were made to, University of Kansas Medical Center Research Institute, Kansas City, Kansas, a research institute affiliated with University of Kansas School of Medicine−Wichita.

WASHINGTON – Obese patients implanted with an intragastric balloon lost significantly more weight than those following a behavioral modification program in a randomized, nonblinded trial.

Moreover, weight loss was preserved even after device removal, study author Dr. Barham Abu Dayyeh said at the annual Digestive Disease Week.

The Orbera intragastric balloon (Apollo Endosurgery) could fill a gap in the United States between obesity lifestyle interventions that are minimally effective and a range of bariatric surgical interventions that are effective, but come at a cost of increased complications and health care costs, he said. Moreover, only 1% of qualified patients actually end up having bariatric surgery.

The silicone, saline-filled intragastric balloon (IGB) has been widely used outside the U.S. for more than 17 years in more than 200,000 patients, added Dr. Abu Dayyeh* of Mayo Clinic in Rochester, Minn.

The multicenter trial was designed for premarketing approval in the U.S. of the Orbera IGB and randomly assigned 273 adults with a body mass index (BMI) of 30-40 kg/m² for more than 2 years to a 12-month behavioral modification program with or without endoscopic placement of the IGB filled to 500-600 cc. The balloon was removed at month 6, with regular office visits through 1 year.

Eighteen patients withdrew before treatment; 215 patients were evaluable at 6 months, 206 at 9 months, and 191 at 12 months. The mean baseline BMI was 35 kg/m² and 90% of patients were female.

At 6 months, the mean percent total body weight loss was greater in the IGB group than the control group (about 10% vs. 4%; P < .001), Dr. Abu Dayyeh said, noting that total body weight loss was significantly higher in the balloon group at each time point: 3, 6, 9, and 12 months.

Similarly, the mean percent of excess weight loss at 6 months was better in the balloon group than in the control group (about 40% vs. 13%; P < .001). The majority of excess weight loss achieved at 6 months was also maintained at 12 months, he said.

At 9 months (3 months after device removal), 45.6% of patients in the IGB group had an excess weight loss at least 15% higher than patients in the control group, which exceeded the 30% threshold set as a primary study outcome, he said.

The mean percent excess weight loss was 26.5% at 9 months in the balloon group, which also exceeded the 25% threshold set as a second primary outcome.

This IGB system “appears to meet the thresholds set forth by the ASGE/ASMBS PIVI for endoscopic bariatric therapies intended as a primary obesity intervention,” Dr. Abu Dayyeh said.

The American Society for Gastrointestinal Endoscopy/American Society for Metabolic and Bariatric Surgery PIVI (Preservation and Incorporation of Valuable endoscopic Innovations) recommends that endoscopic bariatric therapies intended as a primary obesity intervention achieve a mean minimum threshold of 25% excess weight loss at 12 months.

At 52 weeks, both groups had an improvement from baseline in diabetes, hypertension, and lipids, but the improvement was greater with the IGB, he said.

Beck Depression Scores and quality of life also improved in both groups, with the improvement again greater with the IGB.

Serious adverse events were reported by 7% of controls and 9.6% of the balloon group including 8 early removals for intolerance, 1 gastric outlet obstruction, 1 laryngospasm during placement, 1 case of severe abdominal cramping, and 1 case of severe dehydration.

Early device removals occurred in 22% of patients, 15 for symptoms and 13 at subject request, Dr. Abu Dayyeh said. No deaths occurred in the trial.

*Changed on July 8, 2015.

[email protected]

On Twitter @pwendl

WASHINGTON – Obese patients implanted with an intragastric balloon lost significantly more weight than those following a behavioral modification program in a randomized, nonblinded trial.

Moreover, weight loss was preserved even after device removal, study author Dr. Barham Abu Dayyeh said at the annual Digestive Disease Week.

The Orbera intragastric balloon (Apollo Endosurgery) could fill a gap in the United States between obesity lifestyle interventions that are minimally effective and a range of bariatric surgical interventions that are effective, but come at a cost of increased complications and health care costs, he said. Moreover, only 1% of qualified patients actually end up having bariatric surgery.

The silicone, saline-filled intragastric balloon (IGB) has been widely used outside the U.S. for more than 17 years in more than 200,000 patients, added Dr. Abu Dayyeh* of Mayo Clinic in Rochester, Minn.

The multicenter trial was designed for premarketing approval in the U.S. of the Orbera IGB and randomly assigned 273 adults with a body mass index (BMI) of 30-40 kg/m² for more than 2 years to a 12-month behavioral modification program with or without endoscopic placement of the IGB filled to 500-600 cc. The balloon was removed at month 6, with regular office visits through 1 year.

Eighteen patients withdrew before treatment; 215 patients were evaluable at 6 months, 206 at 9 months, and 191 at 12 months. The mean baseline BMI was 35 kg/m² and 90% of patients were female.

At 6 months, the mean percent total body weight loss was greater in the IGB group than the control group (about 10% vs. 4%; P < .001), Dr. Abu Dayyeh said, noting that total body weight loss was significantly higher in the balloon group at each time point: 3, 6, 9, and 12 months.

Similarly, the mean percent of excess weight loss at 6 months was better in the balloon group than in the control group (about 40% vs. 13%; P < .001). The majority of excess weight loss achieved at 6 months was also maintained at 12 months, he said.

At 9 months (3 months after device removal), 45.6% of patients in the IGB group had an excess weight loss at least 15% higher than patients in the control group, which exceeded the 30% threshold set as a primary study outcome, he said.

The mean percent excess weight loss was 26.5% at 9 months in the balloon group, which also exceeded the 25% threshold set as a second primary outcome.

This IGB system “appears to meet the thresholds set forth by the ASGE/ASMBS PIVI for endoscopic bariatric therapies intended as a primary obesity intervention,” Dr. Abu Dayyeh said.

The American Society for Gastrointestinal Endoscopy/American Society for Metabolic and Bariatric Surgery PIVI (Preservation and Incorporation of Valuable endoscopic Innovations) recommends that endoscopic bariatric therapies intended as a primary obesity intervention achieve a mean minimum threshold of 25% excess weight loss at 12 months.

At 52 weeks, both groups had an improvement from baseline in diabetes, hypertension, and lipids, but the improvement was greater with the IGB, he said.

Beck Depression Scores and quality of life also improved in both groups, with the improvement again greater with the IGB.

Serious adverse events were reported by 7% of controls and 9.6% of the balloon group including 8 early removals for intolerance, 1 gastric outlet obstruction, 1 laryngospasm during placement, 1 case of severe abdominal cramping, and 1 case of severe dehydration.

Early device removals occurred in 22% of patients, 15 for symptoms and 13 at subject request, Dr. Abu Dayyeh said. No deaths occurred in the trial.

*Changed on July 8, 2015.

[email protected]

On Twitter @pwendl

WASHINGTON – Obese patients implanted with an intragastric balloon lost significantly more weight than those following a behavioral modification program in a randomized, nonblinded trial.

Moreover, weight loss was preserved even after device removal, study author Dr. Barham Abu Dayyeh said at the annual Digestive Disease Week.

The Orbera intragastric balloon (Apollo Endosurgery) could fill a gap in the United States between obesity lifestyle interventions that are minimally effective and a range of bariatric surgical interventions that are effective, but come at a cost of increased complications and health care costs, he said. Moreover, only 1% of qualified patients actually end up having bariatric surgery.

The silicone, saline-filled intragastric balloon (IGB) has been widely used outside the U.S. for more than 17 years in more than 200,000 patients, added Dr. Abu Dayyeh* of Mayo Clinic in Rochester, Minn.

The multicenter trial was designed for premarketing approval in the U.S. of the Orbera IGB and randomly assigned 273 adults with a body mass index (BMI) of 30-40 kg/m² for more than 2 years to a 12-month behavioral modification program with or without endoscopic placement of the IGB filled to 500-600 cc. The balloon was removed at month 6, with regular office visits through 1 year.

Eighteen patients withdrew before treatment; 215 patients were evaluable at 6 months, 206 at 9 months, and 191 at 12 months. The mean baseline BMI was 35 kg/m² and 90% of patients were female.

At 6 months, the mean percent total body weight loss was greater in the IGB group than the control group (about 10% vs. 4%; P < .001), Dr. Abu Dayyeh said, noting that total body weight loss was significantly higher in the balloon group at each time point: 3, 6, 9, and 12 months.

Similarly, the mean percent of excess weight loss at 6 months was better in the balloon group than in the control group (about 40% vs. 13%; P < .001). The majority of excess weight loss achieved at 6 months was also maintained at 12 months, he said.

At 9 months (3 months after device removal), 45.6% of patients in the IGB group had an excess weight loss at least 15% higher than patients in the control group, which exceeded the 30% threshold set as a primary study outcome, he said.

The mean percent excess weight loss was 26.5% at 9 months in the balloon group, which also exceeded the 25% threshold set as a second primary outcome.

This IGB system “appears to meet the thresholds set forth by the ASGE/ASMBS PIVI for endoscopic bariatric therapies intended as a primary obesity intervention,” Dr. Abu Dayyeh said.

The American Society for Gastrointestinal Endoscopy/American Society for Metabolic and Bariatric Surgery PIVI (Preservation and Incorporation of Valuable endoscopic Innovations) recommends that endoscopic bariatric therapies intended as a primary obesity intervention achieve a mean minimum threshold of 25% excess weight loss at 12 months.

At 52 weeks, both groups had an improvement from baseline in diabetes, hypertension, and lipids, but the improvement was greater with the IGB, he said.

Beck Depression Scores and quality of life also improved in both groups, with the improvement again greater with the IGB.

Serious adverse events were reported by 7% of controls and 9.6% of the balloon group including 8 early removals for intolerance, 1 gastric outlet obstruction, 1 laryngospasm during placement, 1 case of severe abdominal cramping, and 1 case of severe dehydration.

Early device removals occurred in 22% of patients, 15 for symptoms and 13 at subject request, Dr. Abu Dayyeh said. No deaths occurred in the trial.

*Changed on July 8, 2015.

[email protected]

On Twitter @pwendl

Adolescents with slower processing speeds and longer reaction times were at a greater risk of anxiety and depression later in life, according to Catharine R. Gale, Ph.D., of the University of Southampton (England) and her associates.

In this 20-year study of 705 males and females, longer reaction time at 16 years indicated a small but significant association with poorer mental health at age 36.

Adjusting for sex, parental social class, General Health Questionnaire (GHQ) score at age 16 years, health behaviors at age 36 years, and allostatic load had little effect on the association between reaction time and the GHQ score, but the association was weakened with Hospital Anxiety and Depression Scale (HADS) scores for both anxiety and depression. Smoking had a mediating effect on the HADS anxiety score, but not on the depression subscale.

“Further prospective studies of the relation between reaction time and mental health outcomes in other samples are needed to gauge whether reaction time is a true risk factor for mental disorders and to confirm the mediating roles played by smoking and allostatic load,” the investigators noted.

Find the full study in Psychosomatic Medicine (doi:10.1097/PSY.0000000000000189).

[email protected]

Adolescents with slower processing speeds and longer reaction times were at a greater risk of anxiety and depression later in life, according to Catharine R. Gale, Ph.D., of the University of Southampton (England) and her associates.

In this 20-year study of 705 males and females, longer reaction time at 16 years indicated a small but significant association with poorer mental health at age 36.

Adjusting for sex, parental social class, General Health Questionnaire (GHQ) score at age 16 years, health behaviors at age 36 years, and allostatic load had little effect on the association between reaction time and the GHQ score, but the association was weakened with Hospital Anxiety and Depression Scale (HADS) scores for both anxiety and depression. Smoking had a mediating effect on the HADS anxiety score, but not on the depression subscale.

“Further prospective studies of the relation between reaction time and mental health outcomes in other samples are needed to gauge whether reaction time is a true risk factor for mental disorders and to confirm the mediating roles played by smoking and allostatic load,” the investigators noted.

Find the full study in Psychosomatic Medicine (doi:10.1097/PSY.0000000000000189).

[email protected]

Adolescents with slower processing speeds and longer reaction times were at a greater risk of anxiety and depression later in life, according to Catharine R. Gale, Ph.D., of the University of Southampton (England) and her associates.

In this 20-year study of 705 males and females, longer reaction time at 16 years indicated a small but significant association with poorer mental health at age 36.

Adjusting for sex, parental social class, General Health Questionnaire (GHQ) score at age 16 years, health behaviors at age 36 years, and allostatic load had little effect on the association between reaction time and the GHQ score, but the association was weakened with Hospital Anxiety and Depression Scale (HADS) scores for both anxiety and depression. Smoking had a mediating effect on the HADS anxiety score, but not on the depression subscale.

“Further prospective studies of the relation between reaction time and mental health outcomes in other samples are needed to gauge whether reaction time is a true risk factor for mental disorders and to confirm the mediating roles played by smoking and allostatic load,” the investigators noted.

Find the full study in Psychosomatic Medicine (doi:10.1097/PSY.0000000000000189).

[email protected]

Contraceptive pills

Results of a large, retrospective study support the association between newer contraceptive pills and a higher risk of venous thromboembolism (VTE).

The research showed that pills containing one of the newer types of progestogen—drospirenone, desogestrel, gestodene, and cyproterone—are associated with a nearly 2-fold higher risk of VTE than pills containing older progestogens—levonorgestrel, norethisterone, and norgestimate.

The researchers said this study has sufficient power to provide reliable comparative findings for different formulations of combined oral contraceptives. However, because it is an observational study, no definitive conclusions can be drawn about cause and effect.

The team described this research in BMJ alongside a related editorial.

Although the increased risk of VTE associated with combined oral contraceptives has been suggested previously, prior studies have used different methods to examine this link. So the relative risks associated with different combinations remain inconclusive.

Yana Vinogradova, of the University of Nottingham in the UK, and her colleagues tried to address these differences to help explain the range of results.

The team used prescription data from 2 large UK general practice databases to measure the associations between the use of combined oral contraceptives and the risk of VTE in women aged 15 to 49, adjusting for other known VTE risk factors.

The researchers matched 10,562 women with VTE to 42,034 control subjects and found that women who used any combined oral contraceptive within the past year had an increased risk of VTE compared with non-users of similar age and health status. The adjusted odds ratio was 2.97.

The risk of VTE was significantly higher for women who used the newer oral contraceptives than the older pills (P<0.001). The adjusted odds ratios were 4.28 for desogestrel, 4.27 for cyproterone, 4.12 for drospirenone, and 3.64 for gestodene, compared to 2.38 for levonorgestrel, 2.53 for norgestimate, and 2.56 for norethisterone.

The number of extra VTE cases per year per 10,000 treated women was lowest for levonorgestrel and norgestimate (6 cases for both) and highest for desogestrel and cyproterone (14 cases for both).

The researchers said that, although this is an observational study, it has produced the most reliable possible VTE risk estimates using currently available UK prescription data.

Contraceptive pills

Results of a large, retrospective study support the association between newer contraceptive pills and a higher risk of venous thromboembolism (VTE).

The research showed that pills containing one of the newer types of progestogen—drospirenone, desogestrel, gestodene, and cyproterone—are associated with a nearly 2-fold higher risk of VTE than pills containing older progestogens—levonorgestrel, norethisterone, and norgestimate.

The researchers said this study has sufficient power to provide reliable comparative findings for different formulations of combined oral contraceptives. However, because it is an observational study, no definitive conclusions can be drawn about cause and effect.

The team described this research in BMJ alongside a related editorial.

Although the increased risk of VTE associated with combined oral contraceptives has been suggested previously, prior studies have used different methods to examine this link. So the relative risks associated with different combinations remain inconclusive.

Yana Vinogradova, of the University of Nottingham in the UK, and her colleagues tried to address these differences to help explain the range of results.

The team used prescription data from 2 large UK general practice databases to measure the associations between the use of combined oral contraceptives and the risk of VTE in women aged 15 to 49, adjusting for other known VTE risk factors.

The researchers matched 10,562 women with VTE to 42,034 control subjects and found that women who used any combined oral contraceptive within the past year had an increased risk of VTE compared with non-users of similar age and health status. The adjusted odds ratio was 2.97.

The risk of VTE was significantly higher for women who used the newer oral contraceptives than the older pills (P<0.001). The adjusted odds ratios were 4.28 for desogestrel, 4.27 for cyproterone, 4.12 for drospirenone, and 3.64 for gestodene, compared to 2.38 for levonorgestrel, 2.53 for norgestimate, and 2.56 for norethisterone.

The number of extra VTE cases per year per 10,000 treated women was lowest for levonorgestrel and norgestimate (6 cases for both) and highest for desogestrel and cyproterone (14 cases for both).

The researchers said that, although this is an observational study, it has produced the most reliable possible VTE risk estimates using currently available UK prescription data.

Contraceptive pills

Results of a large, retrospective study support the association between newer contraceptive pills and a higher risk of venous thromboembolism (VTE).

The research showed that pills containing one of the newer types of progestogen—drospirenone, desogestrel, gestodene, and cyproterone—are associated with a nearly 2-fold higher risk of VTE than pills containing older progestogens—levonorgestrel, norethisterone, and norgestimate.

The researchers said this study has sufficient power to provide reliable comparative findings for different formulations of combined oral contraceptives. However, because it is an observational study, no definitive conclusions can be drawn about cause and effect.

The team described this research in BMJ alongside a related editorial.

Although the increased risk of VTE associated with combined oral contraceptives has been suggested previously, prior studies have used different methods to examine this link. So the relative risks associated with different combinations remain inconclusive.

Yana Vinogradova, of the University of Nottingham in the UK, and her colleagues tried to address these differences to help explain the range of results.

The team used prescription data from 2 large UK general practice databases to measure the associations between the use of combined oral contraceptives and the risk of VTE in women aged 15 to 49, adjusting for other known VTE risk factors.

The researchers matched 10,562 women with VTE to 42,034 control subjects and found that women who used any combined oral contraceptive within the past year had an increased risk of VTE compared with non-users of similar age and health status. The adjusted odds ratio was 2.97.

The risk of VTE was significantly higher for women who used the newer oral contraceptives than the older pills (P<0.001). The adjusted odds ratios were 4.28 for desogestrel, 4.27 for cyproterone, 4.12 for drospirenone, and 3.64 for gestodene, compared to 2.38 for levonorgestrel, 2.53 for norgestimate, and 2.56 for norethisterone.

The number of extra VTE cases per year per 10,000 treated women was lowest for levonorgestrel and norgestimate (6 cases for both) and highest for desogestrel and cyproterone (14 cases for both).

The researchers said that, although this is an observational study, it has produced the most reliable possible VTE risk estimates using currently available UK prescription data.

Platelets for transfusion

The US Food and Drug Administration (FDA) has expanded the authorized use of Verax Biomedical’s Platelet PGD Test, which detects bacteria in platelets intended for transfusion.

The FDA previously approved the test for leukocyte-reduced apheresis platelets (in 2007) and platelets derived from whole blood (in 2009).

Now, the test has been approved for pre-storage pooled platelets and apheresis platelets in platelet additive solution C (PAS-C) and plasma.

This makes the Platelet PGD Test the only rapid test on the market that can check every commonly distributed platelet type in the US, according to Verax Biomedical.

About the test

The Platelet PGD Test is an immunoassay used on the day of transfusion at the point of care—a hospital or transfusion service—to detect bacterial contamination in platelets to be transfused.

The test consists of a disposable plastic cartridge and 3 pretreatment reagents. To use, the tester pretreats a freshly collected platelet sample (500µL) and applies it to the sample well on the test cartridge.

Lights on the cartridge change from yellow to blue-violet when the test is ready to be interpreted, which is typically about 20 minutes after the sample is applied to the cartridge. The lights confirm that the appropriate volume of a sample was added and the testing is complete.

If the test is positive, a pink line will appear in 1 of the 2 windows on the cartridge. One window represents Gram-positive bacteria and the other Gram-negative. Non-reactive samples will have no line in either window.

Now that the FDA has expanded the indications for the Platelet PGD Test, it can be used as a quality control test for pools of up to 6 units of leukocyte-reduced and non-leukocyte-reduced whole-blood-derived platelets suspended in plasma that are pooled within 4 hours of transfusion.

The test can also be used within 24 hours of transfusion as a safety measure following testing with a growth-based, quality control test cleared by the FDA. For this indication, the Platelet PGD Test can be used with:

• Leukocyte-reduced apheresis platelets suspended in plasma
• Leukocyte-reduced apheresis platelets suspended in PAS-C and plasma
• Pre-storage pools of up to 6 leukocyte-reduced whole-blood-derived platelets suspended in plasma.

In studies conducted by Verax Biomedical (described in the summary document here), the Platelet PGD Test successfully detected bacteria in pre-storage pools of whole-blood derived platelets suspended in plasma and leukocyte-reduced apheresis platelets suspended in plasma or PAS-C and plasma.

Platelets for transfusion

The US Food and Drug Administration (FDA) has expanded the authorized use of Verax Biomedical’s Platelet PGD Test, which detects bacteria in platelets intended for transfusion.

The FDA previously approved the test for leukocyte-reduced apheresis platelets (in 2007) and platelets derived from whole blood (in 2009).

Now, the test has been approved for pre-storage pooled platelets and apheresis platelets in platelet additive solution C (PAS-C) and plasma.

This makes the Platelet PGD Test the only rapid test on the market that can check every commonly distributed platelet type in the US, according to Verax Biomedical.

About the test

The Platelet PGD Test is an immunoassay used on the day of transfusion at the point of care—a hospital or transfusion service—to detect bacterial contamination in platelets to be transfused.

The test consists of a disposable plastic cartridge and 3 pretreatment reagents. To use, the tester pretreats a freshly collected platelet sample (500µL) and applies it to the sample well on the test cartridge.

Lights on the cartridge change from yellow to blue-violet when the test is ready to be interpreted, which is typically about 20 minutes after the sample is applied to the cartridge. The lights confirm that the appropriate volume of a sample was added and the testing is complete.

If the test is positive, a pink line will appear in 1 of the 2 windows on the cartridge. One window represents Gram-positive bacteria and the other Gram-negative. Non-reactive samples will have no line in either window.

Now that the FDA has expanded the indications for the Platelet PGD Test, it can be used as a quality control test for pools of up to 6 units of leukocyte-reduced and non-leukocyte-reduced whole-blood-derived platelets suspended in plasma that are pooled within 4 hours of transfusion.

The test can also be used within 24 hours of transfusion as a safety measure following testing with a growth-based, quality control test cleared by the FDA. For this indication, the Platelet PGD Test can be used with:

• Leukocyte-reduced apheresis platelets suspended in plasma
• Leukocyte-reduced apheresis platelets suspended in PAS-C and plasma
• Pre-storage pools of up to 6 leukocyte-reduced whole-blood-derived platelets suspended in plasma.

In studies conducted by Verax Biomedical (described in the summary document here), the Platelet PGD Test successfully detected bacteria in pre-storage pools of whole-blood derived platelets suspended in plasma and leukocyte-reduced apheresis platelets suspended in plasma or PAS-C and plasma.

Platelets for transfusion

The US Food and Drug Administration (FDA) has expanded the authorized use of Verax Biomedical’s Platelet PGD Test, which detects bacteria in platelets intended for transfusion.

The FDA previously approved the test for leukocyte-reduced apheresis platelets (in 2007) and platelets derived from whole blood (in 2009).

Now, the test has been approved for pre-storage pooled platelets and apheresis platelets in platelet additive solution C (PAS-C) and plasma.

This makes the Platelet PGD Test the only rapid test on the market that can check every commonly distributed platelet type in the US, according to Verax Biomedical.

About the test

The Platelet PGD Test is an immunoassay used on the day of transfusion at the point of care—a hospital or transfusion service—to detect bacterial contamination in platelets to be transfused.

The test consists of a disposable plastic cartridge and 3 pretreatment reagents. To use, the tester pretreats a freshly collected platelet sample (500µL) and applies it to the sample well on the test cartridge.

Lights on the cartridge change from yellow to blue-violet when the test is ready to be interpreted, which is typically about 20 minutes after the sample is applied to the cartridge. The lights confirm that the appropriate volume of a sample was added and the testing is complete.

If the test is positive, a pink line will appear in 1 of the 2 windows on the cartridge. One window represents Gram-positive bacteria and the other Gram-negative. Non-reactive samples will have no line in either window.

Now that the FDA has expanded the indications for the Platelet PGD Test, it can be used as a quality control test for pools of up to 6 units of leukocyte-reduced and non-leukocyte-reduced whole-blood-derived platelets suspended in plasma that are pooled within 4 hours of transfusion.

The test can also be used within 24 hours of transfusion as a safety measure following testing with a growth-based, quality control test cleared by the FDA. For this indication, the Platelet PGD Test can be used with:

• Leukocyte-reduced apheresis platelets suspended in plasma
• Leukocyte-reduced apheresis platelets suspended in PAS-C and plasma
• Pre-storage pools of up to 6 leukocyte-reduced whole-blood-derived platelets suspended in plasma.

In studies conducted by Verax Biomedical (described in the summary document here), the Platelet PGD Test successfully detected bacteria in pre-storage pools of whole-blood derived platelets suspended in plasma and leukocyte-reduced apheresis platelets suspended in plasma or PAS-C and plasma.

Umbilical cord clamping

Photo by Meutia Chaerani

and Indradi Soemardjan

New research suggests that delayed umbilical cord clamping in full-term infants may confer some minor long-term benefits and, at the very least, does not pose any harm.

Delayed clamping did not appear to have a significant effect on most of the mental and physical measures assessed in the study.

It was associated with improved scores in fine-motor skills and social skills at age 4, but these effects only occurred in boys.

Researchers reported these results in JAMA Pediatrics alongside a related editorial.

Previous research has shown that delaying umbilical cord clamping by 2 to 3 minutes after delivery allows fetal blood remaining in the placental circulation to be transfused back to the newborn, and this is associated with improved iron status at 4 to 6 months of age.

However, there is a lack of knowledge regarding the long-term effects of delayed clamping. So policymakers have been hesitant about making clear recommendations regarding cord clamping in full-term infants.

To gain more insight, Ola Andersson, MD, PhD, of Uppsala University in Sweden, and his colleagues performed follow-up assessments of 263 children who were previously enrolled in a randomized trial of cord clamping in full-term infants born in a Swedish hospital.

The team assessed the effects of delayed cord clamping on childhood development at age 4. Delayed clamping (n=141) was defined as occurring 3 or more minutes after delivery, and early clamping (n=122) was defined as occurring 10 seconds or fewer after delivery.

The researchers evaluated child behavior and development using parents’ responses on the Ages and Stages Questionnaire, Third Edition (ASQ), which is used to assess communication, motor skills, and other measures; and the Strengths and Difficulties Questionnaire, which is used to score children’s emotional difficulties, hyperactivity, and other difficulties.

A blinded psychologist also assessed children’s scores on the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III), which is used to assess IQ and similar measures, and the Movement Assessment Battery for Children (Movement ABC), which is used to assess manual dexterity and similar measures.

The researchers found no significant differences between the delayed and early clamping groups with regard to results on the WPPSI-III or the Movement ABC.

However, delayed clamping was associated with a significant improvement over early clamping in ASQ personal-social scores (adjusted mean difference [AMD]=2.8, P=0.006), fine-motor scores (AMD=2.1, P=0.03), and the Strengths and Difficulties Questionnaire prosocial subscale (AMD=0.5, P=0.05).

When the researchers assessed the children according to sex, they found that significant improvements associated with delayed clamping were only present in males.

Males in the delayed clamping group had significantly higher mean scores in tasks involving fine-motor function, including the WPPSI-III processing-speed quotient (AMD=4.2, P=0.02), the Movement ABC bicycle-trail task (AMD=0.8, P=0.03), and fine-motor scores on the ASQ (AMD=4.7, P=0.01). These boys also had significantly higher personal-social scores on the ASQ (AMD=4.9, P=0.004).

The researchers concluded that, although delayed cord clamping and early clamping resulted in similar overall neurodevelopment and behavior among 4-year-old children, there were differences in this study. And this suggests there are some positive, and no harmful, long-term effects of delayed cord clamping.

Umbilical cord clamping

Photo by Meutia Chaerani

and Indradi Soemardjan

New research suggests that delayed umbilical cord clamping in full-term infants may confer some minor long-term benefits and, at the very least, does not pose any harm.

Delayed clamping did not appear to have a significant effect on most of the mental and physical measures assessed in the study.

It was associated with improved scores in fine-motor skills and social skills at age 4, but these effects only occurred in boys.

Researchers reported these results in JAMA Pediatrics alongside a related editorial.

Previous research has shown that delaying umbilical cord clamping by 2 to 3 minutes after delivery allows fetal blood remaining in the placental circulation to be transfused back to the newborn, and this is associated with improved iron status at 4 to 6 months of age.

However, there is a lack of knowledge regarding the long-term effects of delayed clamping. So policymakers have been hesitant about making clear recommendations regarding cord clamping in full-term infants.

To gain more insight, Ola Andersson, MD, PhD, of Uppsala University in Sweden, and his colleagues performed follow-up assessments of 263 children who were previously enrolled in a randomized trial of cord clamping in full-term infants born in a Swedish hospital.

The team assessed the effects of delayed cord clamping on childhood development at age 4. Delayed clamping (n=141) was defined as occurring 3 or more minutes after delivery, and early clamping (n=122) was defined as occurring 10 seconds or fewer after delivery.

The researchers evaluated child behavior and development using parents’ responses on the Ages and Stages Questionnaire, Third Edition (ASQ), which is used to assess communication, motor skills, and other measures; and the Strengths and Difficulties Questionnaire, which is used to score children’s emotional difficulties, hyperactivity, and other difficulties.

A blinded psychologist also assessed children’s scores on the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III), which is used to assess IQ and similar measures, and the Movement Assessment Battery for Children (Movement ABC), which is used to assess manual dexterity and similar measures.

The researchers found no significant differences between the delayed and early clamping groups with regard to results on the WPPSI-III or the Movement ABC.

However, delayed clamping was associated with a significant improvement over early clamping in ASQ personal-social scores (adjusted mean difference [AMD]=2.8, P=0.006), fine-motor scores (AMD=2.1, P=0.03), and the Strengths and Difficulties Questionnaire prosocial subscale (AMD=0.5, P=0.05).

When the researchers assessed the children according to sex, they found that significant improvements associated with delayed clamping were only present in males.

Males in the delayed clamping group had significantly higher mean scores in tasks involving fine-motor function, including the WPPSI-III processing-speed quotient (AMD=4.2, P=0.02), the Movement ABC bicycle-trail task (AMD=0.8, P=0.03), and fine-motor scores on the ASQ (AMD=4.7, P=0.01). These boys also had significantly higher personal-social scores on the ASQ (AMD=4.9, P=0.004).

The researchers concluded that, although delayed cord clamping and early clamping resulted in similar overall neurodevelopment and behavior among 4-year-old children, there were differences in this study. And this suggests there are some positive, and no harmful, long-term effects of delayed cord clamping.

Umbilical cord clamping

Photo by Meutia Chaerani

and Indradi Soemardjan

New research suggests that delayed umbilical cord clamping in full-term infants may confer some minor long-term benefits and, at the very least, does not pose any harm.

Delayed clamping did not appear to have a significant effect on most of the mental and physical measures assessed in the study.

It was associated with improved scores in fine-motor skills and social skills at age 4, but these effects only occurred in boys.

Researchers reported these results in JAMA Pediatrics alongside a related editorial.

Previous research has shown that delaying umbilical cord clamping by 2 to 3 minutes after delivery allows fetal blood remaining in the placental circulation to be transfused back to the newborn, and this is associated with improved iron status at 4 to 6 months of age.

However, there is a lack of knowledge regarding the long-term effects of delayed clamping. So policymakers have been hesitant about making clear recommendations regarding cord clamping in full-term infants.

To gain more insight, Ola Andersson, MD, PhD, of Uppsala University in Sweden, and his colleagues performed follow-up assessments of 263 children who were previously enrolled in a randomized trial of cord clamping in full-term infants born in a Swedish hospital.

The team assessed the effects of delayed cord clamping on childhood development at age 4. Delayed clamping (n=141) was defined as occurring 3 or more minutes after delivery, and early clamping (n=122) was defined as occurring 10 seconds or fewer after delivery.

The researchers evaluated child behavior and development using parents’ responses on the Ages and Stages Questionnaire, Third Edition (ASQ), which is used to assess communication, motor skills, and other measures; and the Strengths and Difficulties Questionnaire, which is used to score children’s emotional difficulties, hyperactivity, and other difficulties.

A blinded psychologist also assessed children’s scores on the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III), which is used to assess IQ and similar measures, and the Movement Assessment Battery for Children (Movement ABC), which is used to assess manual dexterity and similar measures.

The researchers found no significant differences between the delayed and early clamping groups with regard to results on the WPPSI-III or the Movement ABC.

However, delayed clamping was associated with a significant improvement over early clamping in ASQ personal-social scores (adjusted mean difference [AMD]=2.8, P=0.006), fine-motor scores (AMD=2.1, P=0.03), and the Strengths and Difficulties Questionnaire prosocial subscale (AMD=0.5, P=0.05).

When the researchers assessed the children according to sex, they found that significant improvements associated with delayed clamping were only present in males.

Males in the delayed clamping group had significantly higher mean scores in tasks involving fine-motor function, including the WPPSI-III processing-speed quotient (AMD=4.2, P=0.02), the Movement ABC bicycle-trail task (AMD=0.8, P=0.03), and fine-motor scores on the ASQ (AMD=4.7, P=0.01). These boys also had significantly higher personal-social scores on the ASQ (AMD=4.9, P=0.004).

The researchers concluded that, although delayed cord clamping and early clamping resulted in similar overall neurodevelopment and behavior among 4-year-old children, there were differences in this study. And this suggests there are some positive, and no harmful, long-term effects of delayed cord clamping.

DNA coiled around histones

Image by Eric Smith

Researchers say they have identified histone chaperones that play an important role in the structure of chromatin.

The team believes this finding, published in Molecular Cell, could lead to a better understanding of lymphomas and other cancers.

“Maintaining an appropriate chromatin structure is essential for normal development, and, not surprisingly, defects in chromatin components can lead to several diseases,” said study author François Robert, PhD, of Institut de Recherches Cliniques de Montréal in Québec, Canada.

In studying chromatin, Dr Robert and his colleagues have been interested in a histone variant called H2A.Z.

The researchers knew that H2A.Z is incorporated into promoter regions of the gene by SWR-C-related chromatin remodeling complexes, but they wanted to determine if H2A.Z is actively excluded from non-promoter regions.

“With this study, we discovered that 2 other proteins, FACT and Spt6, play an important role in the location of H2A.Z,” said Célia Jeronimo, PhD, a research associate in Dr Robert’s lab.

The team found that FACT and SPt6 both help keep H2A.Z from accumulating in intragenic regions. When either histone chaperone is absent, H2A.Z is mislocalized, which alters chromatin composition and contributes to cryptic transcription.

“Inappropriate H2A.Z localization has previously been observed in cancer cells, but little was understood about the consequences of this phenomenon,” Dr Robert said.

“Although our study was performed in yeast cells, it suggests that mislocalization of H2A.Z may lead to cryptic transcription in some types of cancer such as lymphoma, and this may contribute to the disease. Our next step is therefore to investigate the possible role of H2A.Z and its associated gene expression defects in cancer cells.”

DNA coiled around histones

Image by Eric Smith

Researchers say they have identified histone chaperones that play an important role in the structure of chromatin.

The team believes this finding, published in Molecular Cell, could lead to a better understanding of lymphomas and other cancers.

“Maintaining an appropriate chromatin structure is essential for normal development, and, not surprisingly, defects in chromatin components can lead to several diseases,” said study author François Robert, PhD, of Institut de Recherches Cliniques de Montréal in Québec, Canada.

In studying chromatin, Dr Robert and his colleagues have been interested in a histone variant called H2A.Z.

The researchers knew that H2A.Z is incorporated into promoter regions of the gene by SWR-C-related chromatin remodeling complexes, but they wanted to determine if H2A.Z is actively excluded from non-promoter regions.

“With this study, we discovered that 2 other proteins, FACT and Spt6, play an important role in the location of H2A.Z,” said Célia Jeronimo, PhD, a research associate in Dr Robert’s lab.

The team found that FACT and SPt6 both help keep H2A.Z from accumulating in intragenic regions. When either histone chaperone is absent, H2A.Z is mislocalized, which alters chromatin composition and contributes to cryptic transcription.

“Inappropriate H2A.Z localization has previously been observed in cancer cells, but little was understood about the consequences of this phenomenon,” Dr Robert said.

“Although our study was performed in yeast cells, it suggests that mislocalization of H2A.Z may lead to cryptic transcription in some types of cancer such as lymphoma, and this may contribute to the disease. Our next step is therefore to investigate the possible role of H2A.Z and its associated gene expression defects in cancer cells.”

DNA coiled around histones

Image by Eric Smith

Researchers say they have identified histone chaperones that play an important role in the structure of chromatin.

The team believes this finding, published in Molecular Cell, could lead to a better understanding of lymphomas and other cancers.

“Maintaining an appropriate chromatin structure is essential for normal development, and, not surprisingly, defects in chromatin components can lead to several diseases,” said study author François Robert, PhD, of Institut de Recherches Cliniques de Montréal in Québec, Canada.

In studying chromatin, Dr Robert and his colleagues have been interested in a histone variant called H2A.Z.

The researchers knew that H2A.Z is incorporated into promoter regions of the gene by SWR-C-related chromatin remodeling complexes, but they wanted to determine if H2A.Z is actively excluded from non-promoter regions.

“With this study, we discovered that 2 other proteins, FACT and Spt6, play an important role in the location of H2A.Z,” said Célia Jeronimo, PhD, a research associate in Dr Robert’s lab.

The team found that FACT and SPt6 both help keep H2A.Z from accumulating in intragenic regions. When either histone chaperone is absent, H2A.Z is mislocalized, which alters chromatin composition and contributes to cryptic transcription.

“Inappropriate H2A.Z localization has previously been observed in cancer cells, but little was understood about the consequences of this phenomenon,” Dr Robert said.

“Although our study was performed in yeast cells, it suggests that mislocalization of H2A.Z may lead to cryptic transcription in some types of cancer such as lymphoma, and this may contribute to the disease. Our next step is therefore to investigate the possible role of H2A.Z and its associated gene expression defects in cancer cells.”

Attention deficit/hyperactivity disorder (ADHD) has been identified in children, and appropriate treatments studied now for over half a century. The vast majority of cases that present for treatment do so after the child starts school and concerns are raised about ability to manage academics. Yet, when asked when the symptoms first began, many parents will describe onset prior to the school years – in the preschool period. But identification of ADHD in preschoolers can be difficult because of the developmental changes that are ongoing during the period from 3 to 5 years. Many of the symptoms that one would attribute to ADHD, such as increased motor activity, inattention, and distractibility are commonplace in this age group. Furthermore, some behaviors commonly associated with ADHD, such as emotional lability and obstinacy, are nearly synonymous with being a preschooler. So, how is the diagnosis made? When is it appropriate to treat? And what would that treatment look like? The following case, where symptoms of preschool ADHD go beyond typical development, provides some guides for treatment based on the evolving literature regarding preschool ADHD.

Case Summary

Johnny is a 4-year-old boy who was the product of a complicated pregnancy and delivery. Born at 35 weeks to a 17-year-old mother with a history of tobacco use disorder and depression, he spent several weeks in the special care nursery before leaving the hospital with his mother. His early temperament was described as being “difficult” with frequent episodes of colic and trouble establishing a sleep routine. His father had a history of conduct problems and school failure, and would come in and out of the family for the first 3 years. Lately, he had moved in with Johnny and his mother, and they were trying to “make a go of it.” Johnny had been slightly behind in his developmental milestones – particularly his language – but by 4 years he was able to speak in simple sentences, was able to name his colors, and had started copying circles and squares.

His parents bring Johnny in for an appointment that they made specifically to discuss his activity level and the question of ADHD, which has been brought up by multiple family members and his preschool teacher. They describe some behaviors that you have not heard about previously because they had assumed that “this is what boys did.” At age 3 years, he impulsively ran into the road after being told “no” and was nearly struck by a car. He continually tries to put things into the toaster, and they have had to get “industrial strength” plug covers because he tries to pry them off with a kitchen knife. On multiple occasions, his mother has locked herself in her bedroom because he wouldn’t stop talking to her and she couldn’t stand it anymore. When this happens, she checks often to make sure Johnny is safe, but then calls Johnny’s father home from his job as a delivery driver because she’s at her limit. In fact, Johnny’s father has been called to the preschool to bring Johnny home so many times that his father is in danger of losing his job. While Johnny appears to be a good athlete, he is often picked last for teams because he doesn’t pay attention in the game and likes to “play his own game” of tackling the other children. The stress of raising Johnny is weighing on the parents’ relationship, and Johnny’s father is considering moving out again. The parents ask for an assessment and treatment, preferably with medication.

Case Discussion

Johnny very likely has ADHD. However, to take appropriate caution in the diagnosis, one would consider that he needs to have six of nine criteria of inattention (being careless, difficulty sustaining attention, not listening, not following through, avoiding hard mental tasks, not organizing, losing important items, being easily distractible, and being forgetful) and/or six of nine criteria of hyperactivity/impulsivity (squirming/fidgeting, can’t stay seated, running or climbing excessively, can’t play quietly, “driven by a motor,” talking excessively, blurting out answers, not waiting his turn, and interrupting/intruding on others). As with school-aged ADHD, there need to be symptoms that are frequent (“often”) and that interfere with home, academic, or occupational function. One must take into account the base rate for these symptoms in preschoolers. For example, Willoughby and colleagues (J. Abnorm. Child Psychol. 2012;40:1301-12) demonstrated that at age 4 years, 26.3% of children fidget or squirm, 39.5% act as if “driven by a motor,” 46.3% talk excessively, 28.8% are easily distracted, and 25.4% have difficult waiting their turn. In fact, on average, a 4-year-old will have 1.3 inattentive items and 2.4 hyperactive-impulsive items. Still, Johnny seems to have more than his fair share. This can be validated by a) doing a careful evaluation over time using multiple informants, b) taking a family history, c) looking at developmental signs and ruling out other developmental disorders, d) making physical observations in the office (although these can be deceiving) and e) having the parents and others complete parent and caregiver checklists.

When asking parents and caregivers to complete checklists, it is crucial to make sure that these checklists look for symptoms other than just ADHD, because there are often co-occurring symptoms and disorders. These include oppositional defiant disorder, anxiety, obsessive compulsive disorder, depressive disorders, autism spectrum disorders, trauma, and learning/communication disorders. In fact, the Preschool ADHD Treatment Study (PATS) demonstrated that 71.5% of children with preschool ADHD had at least one other diagnosis and 29.7% had two or more (J. Child Adolesc. Psychopharmacol. 2007;17:563-80). Use of a broad-based instrument that captures all of these domains, in addition to attention, is warranted. In our clinic, we also assess the parents for psychopathology using the same instruments. The reason for this is, first, that family history increases the likelihood of an ADHD diagnosis and, perhaps more importantly, presence of family psychopathology makes treatment more difficult. This is because the treatment you will prescribe is going to actively involve the parents.

The treatment of choice for preschool ADHD, based on practice parameters and expert opinion, is to start with family-based behavioral treatments. There are now several empirically-based treatments that have shown efficacy for the symptoms of inattention and hyperactivity-impulsivity in preschoolers. These include Triple P (“Practitioner’s Manual for Enhanced Triple P” [Brisbane: Families International Publishing, 1998]), The Incredible Years (Webster-Stratton & Hancock, 1998), and the Revised New Forest Parent Program (Daley & Thompson, 2007), among others. If these are not available in your community, other options would be “Helping the noncompliant child: A clinician’s guide to effective parent training,” 2nd ed. (The Guilford Press: New York, 2003) or any other empirically-based parent training program. This is why it is critical to engage the parents in treatment and to refer them for treatment for their own psychopathology, if present. Furthermore, engaging the family in a program of wellness (freedom from substances, enhanced nutrition, avoidance of artificial food coloring, increased exercise), has less of a research base, but the available evidence is that it is helpful.

If medications become necessary because of safety concerns, there are few options that have a Food and Drug Administration indication. Those that do have an indication for disruptive behavior below the age of 5 years (haloperidol, dextroamphetamine, chlorpromazine, and risperidone) should not be considered as first line. The PATS study demonstrated the safety and efficacy of methylphenidate, but with optimal doses lower than those seen in school-aged children (0.7 mg/kg per day) and with increased numbers of adverse effects (11% discontinuing) (J. Am. Acad. Child Adolesc. Psychiatry 2006;45:1284-93; J. Am. Acad. Child Adolesc. Psychiatry 2006;45:1294-303).

Because of the increased amount of side effects, medication treatment cannot be considered as the first treatment. Treatment with nonstimulants is poorly studied. Any treatment with methylphenidate would be considered off-label prescribing, which must be done with great caution and, preferably, in consultation with a child and adolescent psychiatrist.

The diagnosis and management of ADHD in the very young is tricky, but possible. Doing a comprehensive evaluation with information from multiple informants, assessing and treating the parents for psychopathology, engaging the family in wellness, and starting with behavioral management is the way to go. If you feel that medication treatment is necessary for safety of the little ones, it’s best to consult, because none of the medications with FDA indication are likely to be the answer.

Dr. Althoff is associate professor of psychiatry, psychology, and pediatrics at the University of Vermont, Burlington. He is director of the division of behavioral genetics and conducts research on the development of self-regulation in children. Dr. Althoff receives no funding from pharmaceutical companies or industry. He has grant funding from the National Institute of General Medical Sciences and the Klingenstein Third Generation Foundation, and is employed, in part, by the nonprofit Research Center for Children, Youth, and Families that develops the Child Behavior Checklist and associated instruments. E-mail him at [email protected].

Attention deficit/hyperactivity disorder (ADHD) has been identified in children, and appropriate treatments studied now for over half a century. The vast majority of cases that present for treatment do so after the child starts school and concerns are raised about ability to manage academics. Yet, when asked when the symptoms first began, many parents will describe onset prior to the school years – in the preschool period. But identification of ADHD in preschoolers can be difficult because of the developmental changes that are ongoing during the period from 3 to 5 years. Many of the symptoms that one would attribute to ADHD, such as increased motor activity, inattention, and distractibility are commonplace in this age group. Furthermore, some behaviors commonly associated with ADHD, such as emotional lability and obstinacy, are nearly synonymous with being a preschooler. So, how is the diagnosis made? When is it appropriate to treat? And what would that treatment look like? The following case, where symptoms of preschool ADHD go beyond typical development, provides some guides for treatment based on the evolving literature regarding preschool ADHD.

Case Summary

Johnny is a 4-year-old boy who was the product of a complicated pregnancy and delivery. Born at 35 weeks to a 17-year-old mother with a history of tobacco use disorder and depression, he spent several weeks in the special care nursery before leaving the hospital with his mother. His early temperament was described as being “difficult” with frequent episodes of colic and trouble establishing a sleep routine. His father had a history of conduct problems and school failure, and would come in and out of the family for the first 3 years. Lately, he had moved in with Johnny and his mother, and they were trying to “make a go of it.” Johnny had been slightly behind in his developmental milestones – particularly his language – but by 4 years he was able to speak in simple sentences, was able to name his colors, and had started copying circles and squares.

His parents bring Johnny in for an appointment that they made specifically to discuss his activity level and the question of ADHD, which has been brought up by multiple family members and his preschool teacher. They describe some behaviors that you have not heard about previously because they had assumed that “this is what boys did.” At age 3 years, he impulsively ran into the road after being told “no” and was nearly struck by a car. He continually tries to put things into the toaster, and they have had to get “industrial strength” plug covers because he tries to pry them off with a kitchen knife. On multiple occasions, his mother has locked herself in her bedroom because he wouldn’t stop talking to her and she couldn’t stand it anymore. When this happens, she checks often to make sure Johnny is safe, but then calls Johnny’s father home from his job as a delivery driver because she’s at her limit. In fact, Johnny’s father has been called to the preschool to bring Johnny home so many times that his father is in danger of losing his job. While Johnny appears to be a good athlete, he is often picked last for teams because he doesn’t pay attention in the game and likes to “play his own game” of tackling the other children. The stress of raising Johnny is weighing on the parents’ relationship, and Johnny’s father is considering moving out again. The parents ask for an assessment and treatment, preferably with medication.

Case Discussion

Johnny very likely has ADHD. However, to take appropriate caution in the diagnosis, one would consider that he needs to have six of nine criteria of inattention (being careless, difficulty sustaining attention, not listening, not following through, avoiding hard mental tasks, not organizing, losing important items, being easily distractible, and being forgetful) and/or six of nine criteria of hyperactivity/impulsivity (squirming/fidgeting, can’t stay seated, running or climbing excessively, can’t play quietly, “driven by a motor,” talking excessively, blurting out answers, not waiting his turn, and interrupting/intruding on others). As with school-aged ADHD, there need to be symptoms that are frequent (“often”) and that interfere with home, academic, or occupational function. One must take into account the base rate for these symptoms in preschoolers. For example, Willoughby and colleagues (J. Abnorm. Child Psychol. 2012;40:1301-12) demonstrated that at age 4 years, 26.3% of children fidget or squirm, 39.5% act as if “driven by a motor,” 46.3% talk excessively, 28.8% are easily distracted, and 25.4% have difficult waiting their turn. In fact, on average, a 4-year-old will have 1.3 inattentive items and 2.4 hyperactive-impulsive items. Still, Johnny seems to have more than his fair share. This can be validated by a) doing a careful evaluation over time using multiple informants, b) taking a family history, c) looking at developmental signs and ruling out other developmental disorders, d) making physical observations in the office (although these can be deceiving) and e) having the parents and others complete parent and caregiver checklists.

When asking parents and caregivers to complete checklists, it is crucial to make sure that these checklists look for symptoms other than just ADHD, because there are often co-occurring symptoms and disorders. These include oppositional defiant disorder, anxiety, obsessive compulsive disorder, depressive disorders, autism spectrum disorders, trauma, and learning/communication disorders. In fact, the Preschool ADHD Treatment Study (PATS) demonstrated that 71.5% of children with preschool ADHD had at least one other diagnosis and 29.7% had two or more (J. Child Adolesc. Psychopharmacol. 2007;17:563-80). Use of a broad-based instrument that captures all of these domains, in addition to attention, is warranted. In our clinic, we also assess the parents for psychopathology using the same instruments. The reason for this is, first, that family history increases the likelihood of an ADHD diagnosis and, perhaps more importantly, presence of family psychopathology makes treatment more difficult. This is because the treatment you will prescribe is going to actively involve the parents.

The treatment of choice for preschool ADHD, based on practice parameters and expert opinion, is to start with family-based behavioral treatments. There are now several empirically-based treatments that have shown efficacy for the symptoms of inattention and hyperactivity-impulsivity in preschoolers. These include Triple P (“Practitioner’s Manual for Enhanced Triple P” [Brisbane: Families International Publishing, 1998]), The Incredible Years (Webster-Stratton & Hancock, 1998), and the Revised New Forest Parent Program (Daley & Thompson, 2007), among others. If these are not available in your community, other options would be “Helping the noncompliant child: A clinician’s guide to effective parent training,” 2nd ed. (The Guilford Press: New York, 2003) or any other empirically-based parent training program. This is why it is critical to engage the parents in treatment and to refer them for treatment for their own psychopathology, if present. Furthermore, engaging the family in a program of wellness (freedom from substances, enhanced nutrition, avoidance of artificial food coloring, increased exercise), has less of a research base, but the available evidence is that it is helpful.

If medications become necessary because of safety concerns, there are few options that have a Food and Drug Administration indication. Those that do have an indication for disruptive behavior below the age of 5 years (haloperidol, dextroamphetamine, chlorpromazine, and risperidone) should not be considered as first line. The PATS study demonstrated the safety and efficacy of methylphenidate, but with optimal doses lower than those seen in school-aged children (0.7 mg/kg per day) and with increased numbers of adverse effects (11% discontinuing) (J. Am. Acad. Child Adolesc. Psychiatry 2006;45:1284-93; J. Am. Acad. Child Adolesc. Psychiatry 2006;45:1294-303).

Because of the increased amount of side effects, medication treatment cannot be considered as the first treatment. Treatment with nonstimulants is poorly studied. Any treatment with methylphenidate would be considered off-label prescribing, which must be done with great caution and, preferably, in consultation with a child and adolescent psychiatrist.

The diagnosis and management of ADHD in the very young is tricky, but possible. Doing a comprehensive evaluation with information from multiple informants, assessing and treating the parents for psychopathology, engaging the family in wellness, and starting with behavioral management is the way to go. If you feel that medication treatment is necessary for safety of the little ones, it’s best to consult, because none of the medications with FDA indication are likely to be the answer.

Dr. Althoff is associate professor of psychiatry, psychology, and pediatrics at the University of Vermont, Burlington. He is director of the division of behavioral genetics and conducts research on the development of self-regulation in children. Dr. Althoff receives no funding from pharmaceutical companies or industry. He has grant funding from the National Institute of General Medical Sciences and the Klingenstein Third Generation Foundation, and is employed, in part, by the nonprofit Research Center for Children, Youth, and Families that develops the Child Behavior Checklist and associated instruments. E-mail him at [email protected].

Attention deficit/hyperactivity disorder (ADHD) has been identified in children, and appropriate treatments studied now for over half a century. The vast majority of cases that present for treatment do so after the child starts school and concerns are raised about ability to manage academics. Yet, when asked when the symptoms first began, many parents will describe onset prior to the school years – in the preschool period. But identification of ADHD in preschoolers can be difficult because of the developmental changes that are ongoing during the period from 3 to 5 years. Many of the symptoms that one would attribute to ADHD, such as increased motor activity, inattention, and distractibility are commonplace in this age group. Furthermore, some behaviors commonly associated with ADHD, such as emotional lability and obstinacy, are nearly synonymous with being a preschooler. So, how is the diagnosis made? When is it appropriate to treat? And what would that treatment look like? The following case, where symptoms of preschool ADHD go beyond typical development, provides some guides for treatment based on the evolving literature regarding preschool ADHD.

Case Summary

Johnny is a 4-year-old boy who was the product of a complicated pregnancy and delivery. Born at 35 weeks to a 17-year-old mother with a history of tobacco use disorder and depression, he spent several weeks in the special care nursery before leaving the hospital with his mother. His early temperament was described as being “difficult” with frequent episodes of colic and trouble establishing a sleep routine. His father had a history of conduct problems and school failure, and would come in and out of the family for the first 3 years. Lately, he had moved in with Johnny and his mother, and they were trying to “make a go of it.” Johnny had been slightly behind in his developmental milestones – particularly his language – but by 4 years he was able to speak in simple sentences, was able to name his colors, and had started copying circles and squares.

His parents bring Johnny in for an appointment that they made specifically to discuss his activity level and the question of ADHD, which has been brought up by multiple family members and his preschool teacher. They describe some behaviors that you have not heard about previously because they had assumed that “this is what boys did.” At age 3 years, he impulsively ran into the road after being told “no” and was nearly struck by a car. He continually tries to put things into the toaster, and they have had to get “industrial strength” plug covers because he tries to pry them off with a kitchen knife. On multiple occasions, his mother has locked herself in her bedroom because he wouldn’t stop talking to her and she couldn’t stand it anymore. When this happens, she checks often to make sure Johnny is safe, but then calls Johnny’s father home from his job as a delivery driver because she’s at her limit. In fact, Johnny’s father has been called to the preschool to bring Johnny home so many times that his father is in danger of losing his job. While Johnny appears to be a good athlete, he is often picked last for teams because he doesn’t pay attention in the game and likes to “play his own game” of tackling the other children. The stress of raising Johnny is weighing on the parents’ relationship, and Johnny’s father is considering moving out again. The parents ask for an assessment and treatment, preferably with medication.

Case Discussion

Johnny very likely has ADHD. However, to take appropriate caution in the diagnosis, one would consider that he needs to have six of nine criteria of inattention (being careless, difficulty sustaining attention, not listening, not following through, avoiding hard mental tasks, not organizing, losing important items, being easily distractible, and being forgetful) and/or six of nine criteria of hyperactivity/impulsivity (squirming/fidgeting, can’t stay seated, running or climbing excessively, can’t play quietly, “driven by a motor,” talking excessively, blurting out answers, not waiting his turn, and interrupting/intruding on others). As with school-aged ADHD, there need to be symptoms that are frequent (“often”) and that interfere with home, academic, or occupational function. One must take into account the base rate for these symptoms in preschoolers. For example, Willoughby and colleagues (J. Abnorm. Child Psychol. 2012;40:1301-12) demonstrated that at age 4 years, 26.3% of children fidget or squirm, 39.5% act as if “driven by a motor,” 46.3% talk excessively, 28.8% are easily distracted, and 25.4% have difficult waiting their turn. In fact, on average, a 4-year-old will have 1.3 inattentive items and 2.4 hyperactive-impulsive items. Still, Johnny seems to have more than his fair share. This can be validated by a) doing a careful evaluation over time using multiple informants, b) taking a family history, c) looking at developmental signs and ruling out other developmental disorders, d) making physical observations in the office (although these can be deceiving) and e) having the parents and others complete parent and caregiver checklists.

When asking parents and caregivers to complete checklists, it is crucial to make sure that these checklists look for symptoms other than just ADHD, because there are often co-occurring symptoms and disorders. These include oppositional defiant disorder, anxiety, obsessive compulsive disorder, depressive disorders, autism spectrum disorders, trauma, and learning/communication disorders. In fact, the Preschool ADHD Treatment Study (PATS) demonstrated that 71.5% of children with preschool ADHD had at least one other diagnosis and 29.7% had two or more (J. Child Adolesc. Psychopharmacol. 2007;17:563-80). Use of a broad-based instrument that captures all of these domains, in addition to attention, is warranted. In our clinic, we also assess the parents for psychopathology using the same instruments. The reason for this is, first, that family history increases the likelihood of an ADHD diagnosis and, perhaps more importantly, presence of family psychopathology makes treatment more difficult. This is because the treatment you will prescribe is going to actively involve the parents.

The treatment of choice for preschool ADHD, based on practice parameters and expert opinion, is to start with family-based behavioral treatments. There are now several empirically-based treatments that have shown efficacy for the symptoms of inattention and hyperactivity-impulsivity in preschoolers. These include Triple P (“Practitioner’s Manual for Enhanced Triple P” [Brisbane: Families International Publishing, 1998]), The Incredible Years (Webster-Stratton & Hancock, 1998), and the Revised New Forest Parent Program (Daley & Thompson, 2007), among others. If these are not available in your community, other options would be “Helping the noncompliant child: A clinician’s guide to effective parent training,” 2nd ed. (The Guilford Press: New York, 2003) or any other empirically-based parent training program. This is why it is critical to engage the parents in treatment and to refer them for treatment for their own psychopathology, if present. Furthermore, engaging the family in a program of wellness (freedom from substances, enhanced nutrition, avoidance of artificial food coloring, increased exercise), has less of a research base, but the available evidence is that it is helpful.

If medications become necessary because of safety concerns, there are few options that have a Food and Drug Administration indication. Those that do have an indication for disruptive behavior below the age of 5 years (haloperidol, dextroamphetamine, chlorpromazine, and risperidone) should not be considered as first line. The PATS study demonstrated the safety and efficacy of methylphenidate, but with optimal doses lower than those seen in school-aged children (0.7 mg/kg per day) and with increased numbers of adverse effects (11% discontinuing) (J. Am. Acad. Child Adolesc. Psychiatry 2006;45:1284-93; J. Am. Acad. Child Adolesc. Psychiatry 2006;45:1294-303).

Because of the increased amount of side effects, medication treatment cannot be considered as the first treatment. Treatment with nonstimulants is poorly studied. Any treatment with methylphenidate would be considered off-label prescribing, which must be done with great caution and, preferably, in consultation with a child and adolescent psychiatrist.

The diagnosis and management of ADHD in the very young is tricky, but possible. Doing a comprehensive evaluation with information from multiple informants, assessing and treating the parents for psychopathology, engaging the family in wellness, and starting with behavioral management is the way to go. If you feel that medication treatment is necessary for safety of the little ones, it’s best to consult, because none of the medications with FDA indication are likely to be the answer.

Dr. Althoff is associate professor of psychiatry, psychology, and pediatrics at the University of Vermont, Burlington. He is director of the division of behavioral genetics and conducts research on the development of self-regulation in children. Dr. Althoff receives no funding from pharmaceutical companies or industry. He has grant funding from the National Institute of General Medical Sciences and the Klingenstein Third Generation Foundation, and is employed, in part, by the nonprofit Research Center for Children, Youth, and Families that develops the Child Behavior Checklist and associated instruments. E-mail him at [email protected].