Alzheimer's & Cognition

SAN DIEGO – Emerging biomarkers and treatments offer more options to diagnose and manage Alzheimer’s disease (AD) and related dementias, but high costs and potentially serious complications mean using them with caution, said a presenter at the annual meeting of the American College of Physicians.

Dementia prevalence is increasing as the proportion of the U.S. population older than 65 rises, said Zaldy Tan, MD, professor of neurology at Cedars-Sinai Medical Center, Los Angeles. AD deaths more than doubled between 2000 and 2018, he noted, while deaths from HIV infection, stroke, and heart disease decreased.

Most people in the United States who have AD are White, but studies suggest that, compared with Whites, the risk of AD is two times higher in Blacks and 1.5 times higher in Hispanics . “These data suggest that both genes and social determinants of health are at play,” Dr. Tan said.
 

Diagnosis of Alzheimer’s disease

The different types of dementia make it challenging for primary care physicians to identify the cause of cognitive impairment. “Even though AD is the most common type, clinicians should keep in mind that another type of dementia may be the cause of cognitive impairment,” Dr. Tan cautioned. Other dementia diagnoses include vascular, Lewy body, and frontotemporal.

Diagnostic criteria for AD include evidence of significant cognitive decline in at least one cognitive domain that interferes with independence in everyday activities, as well as the absence of another mental disorder or delirium that would explain the cognitive deficits.

“We see many patients with depressive symptoms and mild cognitive impairment, and it is not always easy to tell which of them have dementia because of the overlap in the symptoms of depression and AD,” said internist Roderick Kim, MD, of Grand Rapids, Mich., who attended the session.

It can be challenging to convince patients to undergo the appropriate diagnostic workup, Dr. Kim said. “This can delay treatment, so it is important to explain to patients that cognitive decline can progress quickly and that there are treatment options to slow it down.”
 

Why do we need biomarkers for Alzheimer’s disease?

AD is characterized by a long preclinical phase with no specific symptoms other than the typical signs and symptoms of aging, Dr. Tan said. That means cognitive impairment progresses rapidly after diagnosis in most patients with AD.

“In most cases, an accurate history, physical and neurologic examinations, basic labs, and neuroimaging are sufficient for memory loss evaluation. However, as more disease-modifying therapies come to market, biomarkers will rise in importance in primary care,” he said.

This long asymptomatic phase of AD creates the need for diagnostic biomarkers for an earlier diagnosis, he said. Amyloid-beta and tau deposits in PET images and the levels of amyloid-beta seeds, phosphorylated tau, and neurofilament light chain in the cerebrospinal fluid can be used as diagnostic biomarkers in patients with suspected AD. Emerging blood biomarkers for earlier detection include the levels of amyloid-beta_1–42, phosphorylated tau, and neurofilament light chain.

With biomarkers and other new tools for the diagnosis of dementia in primary care, Dr. Tan said: “The greatest challenge is cost, as blood-based biomarkers are not currently covered by insurance and still rather costly. In addition, blood-based biomarkers will need to receive [Food and Drug Administration] approval in order to have more widespread availability.”


 

New and emerging therapies for Alzheimer’s disease

There are two classes of FDA-approved medications to manage cognitive symptoms of dementia: acetylcholinesterase inhibitors and N-methyl-D-aspartate receptor antagonists. The selections may be trial and error for each patient, Dr. Tan said.

“The approved medications can exert subtle benefits that are clinically observable. Thus, barring any contraindications or intolerance, most patients with AD would benefit from a trial of one or both of these medication classes,” said Dr. Tan. He added that it is equally important to wean off and discontinue these medications if there is intolerance or lack of a subjective or objective beneficial response.

Other medications are available for some of the most common behavioral problems associated with dementia, such as agitation, depression, and disorientation. Dr. Tan advised not to prescribe behavioral medications until nonpharmacologic interventions prove to be ineffective or impractical. Behavioral medications have many side effects, some of which are potentially serious, he said, so the risk-benefit ratio should be considered.

In his own practice, when nonpharmacologic strategies do not improve the behavioral symptoms of dementia, Dr. Tan said that, “in cases where a person is at risk of harm to themselves or others, a discussion with the patient and their caregivers about the pros and cons of medications to treat the behavior need to be had. Careful monitoring of the response and dose escalation or deprescribing when appropriate is important to keep in mind.”

Disease-modifying agents have recently provided new hope for AD treatment. Aducanumab and lecanemab, both monoclonal antibodies that target amyloids, are the first two drugs that received accelerated FDA approval for AD.

Although these monoclonal antibodies can help clear deposited amyloid plaques and show some benefit in slowing cognitive impairment in clinical trials, the real-world benefits were unclear enough for Medicare to limit coverage to people enrolled in approved studies to gather more data. Additionally, these agents can cause potentially amyloid-related imaging abnormalities, which may indicate edema, effusion, or microhemorrhage. Therefore, clinicians need to have a clear conversation of risks and benefits with patients and caregivers about these treatments.
 

Looking ahead

When asked about the most promising emerging technologies or techniques related to dementia diagnosis and management, Dr. Tan noted that multiple technology companies and start-ups are looking for new ways to detect dementia earlier or keep persons with dementia safe at home. Some devices deliver brain waves, computerized brain games or tests, automated pill dispensers, and fall monitors.

“Some of these are potentially helpful, but not every person with dementia will benefit. In addition, most of these technologies are out-of-pocket expenses for the patients and their families. It is important to know what is out there but also be cautious about outrageous claims,” he added.

Dr. Tan reported no relationships with entities whose primary business is producing, marketing, selling, reselling, or distributing health care products used by or on patients.

SAN DIEGO – Emerging biomarkers and treatments offer more options to diagnose and manage Alzheimer’s disease (AD) and related dementias, but high costs and potentially serious complications mean using them with caution, said a presenter at the annual meeting of the American College of Physicians.

Dementia prevalence is increasing as the proportion of the U.S. population older than 65 rises, said Zaldy Tan, MD, professor of neurology at Cedars-Sinai Medical Center, Los Angeles. AD deaths more than doubled between 2000 and 2018, he noted, while deaths from HIV infection, stroke, and heart disease decreased.

Most people in the United States who have AD are White, but studies suggest that, compared with Whites, the risk of AD is two times higher in Blacks and 1.5 times higher in Hispanics . “These data suggest that both genes and social determinants of health are at play,” Dr. Tan said.
 

Diagnosis of Alzheimer’s disease

The different types of dementia make it challenging for primary care physicians to identify the cause of cognitive impairment. “Even though AD is the most common type, clinicians should keep in mind that another type of dementia may be the cause of cognitive impairment,” Dr. Tan cautioned. Other dementia diagnoses include vascular, Lewy body, and frontotemporal.

Diagnostic criteria for AD include evidence of significant cognitive decline in at least one cognitive domain that interferes with independence in everyday activities, as well as the absence of another mental disorder or delirium that would explain the cognitive deficits.

“We see many patients with depressive symptoms and mild cognitive impairment, and it is not always easy to tell which of them have dementia because of the overlap in the symptoms of depression and AD,” said internist Roderick Kim, MD, of Grand Rapids, Mich., who attended the session.

It can be challenging to convince patients to undergo the appropriate diagnostic workup, Dr. Kim said. “This can delay treatment, so it is important to explain to patients that cognitive decline can progress quickly and that there are treatment options to slow it down.”
 

Why do we need biomarkers for Alzheimer’s disease?

AD is characterized by a long preclinical phase with no specific symptoms other than the typical signs and symptoms of aging, Dr. Tan said. That means cognitive impairment progresses rapidly after diagnosis in most patients with AD.

“In most cases, an accurate history, physical and neurologic examinations, basic labs, and neuroimaging are sufficient for memory loss evaluation. However, as more disease-modifying therapies come to market, biomarkers will rise in importance in primary care,” he said.

This long asymptomatic phase of AD creates the need for diagnostic biomarkers for an earlier diagnosis, he said. Amyloid-beta and tau deposits in PET images and the levels of amyloid-beta seeds, phosphorylated tau, and neurofilament light chain in the cerebrospinal fluid can be used as diagnostic biomarkers in patients with suspected AD. Emerging blood biomarkers for earlier detection include the levels of amyloid-beta_1–42, phosphorylated tau, and neurofilament light chain.

With biomarkers and other new tools for the diagnosis of dementia in primary care, Dr. Tan said: “The greatest challenge is cost, as blood-based biomarkers are not currently covered by insurance and still rather costly. In addition, blood-based biomarkers will need to receive [Food and Drug Administration] approval in order to have more widespread availability.”


 

New and emerging therapies for Alzheimer’s disease

There are two classes of FDA-approved medications to manage cognitive symptoms of dementia: acetylcholinesterase inhibitors and N-methyl-D-aspartate receptor antagonists. The selections may be trial and error for each patient, Dr. Tan said.

“The approved medications can exert subtle benefits that are clinically observable. Thus, barring any contraindications or intolerance, most patients with AD would benefit from a trial of one or both of these medication classes,” said Dr. Tan. He added that it is equally important to wean off and discontinue these medications if there is intolerance or lack of a subjective or objective beneficial response.

Other medications are available for some of the most common behavioral problems associated with dementia, such as agitation, depression, and disorientation. Dr. Tan advised not to prescribe behavioral medications until nonpharmacologic interventions prove to be ineffective or impractical. Behavioral medications have many side effects, some of which are potentially serious, he said, so the risk-benefit ratio should be considered.

In his own practice, when nonpharmacologic strategies do not improve the behavioral symptoms of dementia, Dr. Tan said that, “in cases where a person is at risk of harm to themselves or others, a discussion with the patient and their caregivers about the pros and cons of medications to treat the behavior need to be had. Careful monitoring of the response and dose escalation or deprescribing when appropriate is important to keep in mind.”

Disease-modifying agents have recently provided new hope for AD treatment. Aducanumab and lecanemab, both monoclonal antibodies that target amyloids, are the first two drugs that received accelerated FDA approval for AD.

Although these monoclonal antibodies can help clear deposited amyloid plaques and show some benefit in slowing cognitive impairment in clinical trials, the real-world benefits were unclear enough for Medicare to limit coverage to people enrolled in approved studies to gather more data. Additionally, these agents can cause potentially amyloid-related imaging abnormalities, which may indicate edema, effusion, or microhemorrhage. Therefore, clinicians need to have a clear conversation of risks and benefits with patients and caregivers about these treatments.
 

Looking ahead

When asked about the most promising emerging technologies or techniques related to dementia diagnosis and management, Dr. Tan noted that multiple technology companies and start-ups are looking for new ways to detect dementia earlier or keep persons with dementia safe at home. Some devices deliver brain waves, computerized brain games or tests, automated pill dispensers, and fall monitors.

“Some of these are potentially helpful, but not every person with dementia will benefit. In addition, most of these technologies are out-of-pocket expenses for the patients and their families. It is important to know what is out there but also be cautious about outrageous claims,” he added.

Dr. Tan reported no relationships with entities whose primary business is producing, marketing, selling, reselling, or distributing health care products used by or on patients.

SAN DIEGO – Emerging biomarkers and treatments offer more options to diagnose and manage Alzheimer’s disease (AD) and related dementias, but high costs and potentially serious complications mean using them with caution, said a presenter at the annual meeting of the American College of Physicians.

Dementia prevalence is increasing as the proportion of the U.S. population older than 65 rises, said Zaldy Tan, MD, professor of neurology at Cedars-Sinai Medical Center, Los Angeles. AD deaths more than doubled between 2000 and 2018, he noted, while deaths from HIV infection, stroke, and heart disease decreased.

Most people in the United States who have AD are White, but studies suggest that, compared with Whites, the risk of AD is two times higher in Blacks and 1.5 times higher in Hispanics . “These data suggest that both genes and social determinants of health are at play,” Dr. Tan said.
 

Diagnosis of Alzheimer’s disease

The different types of dementia make it challenging for primary care physicians to identify the cause of cognitive impairment. “Even though AD is the most common type, clinicians should keep in mind that another type of dementia may be the cause of cognitive impairment,” Dr. Tan cautioned. Other dementia diagnoses include vascular, Lewy body, and frontotemporal.

Diagnostic criteria for AD include evidence of significant cognitive decline in at least one cognitive domain that interferes with independence in everyday activities, as well as the absence of another mental disorder or delirium that would explain the cognitive deficits.

“We see many patients with depressive symptoms and mild cognitive impairment, and it is not always easy to tell which of them have dementia because of the overlap in the symptoms of depression and AD,” said internist Roderick Kim, MD, of Grand Rapids, Mich., who attended the session.

It can be challenging to convince patients to undergo the appropriate diagnostic workup, Dr. Kim said. “This can delay treatment, so it is important to explain to patients that cognitive decline can progress quickly and that there are treatment options to slow it down.”
 

Why do we need biomarkers for Alzheimer’s disease?

AD is characterized by a long preclinical phase with no specific symptoms other than the typical signs and symptoms of aging, Dr. Tan said. That means cognitive impairment progresses rapidly after diagnosis in most patients with AD.

“In most cases, an accurate history, physical and neurologic examinations, basic labs, and neuroimaging are sufficient for memory loss evaluation. However, as more disease-modifying therapies come to market, biomarkers will rise in importance in primary care,” he said.

This long asymptomatic phase of AD creates the need for diagnostic biomarkers for an earlier diagnosis, he said. Amyloid-beta and tau deposits in PET images and the levels of amyloid-beta seeds, phosphorylated tau, and neurofilament light chain in the cerebrospinal fluid can be used as diagnostic biomarkers in patients with suspected AD. Emerging blood biomarkers for earlier detection include the levels of amyloid-beta_1–42, phosphorylated tau, and neurofilament light chain.

With biomarkers and other new tools for the diagnosis of dementia in primary care, Dr. Tan said: “The greatest challenge is cost, as blood-based biomarkers are not currently covered by insurance and still rather costly. In addition, blood-based biomarkers will need to receive [Food and Drug Administration] approval in order to have more widespread availability.”


 

New and emerging therapies for Alzheimer’s disease

There are two classes of FDA-approved medications to manage cognitive symptoms of dementia: acetylcholinesterase inhibitors and N-methyl-D-aspartate receptor antagonists. The selections may be trial and error for each patient, Dr. Tan said.

“The approved medications can exert subtle benefits that are clinically observable. Thus, barring any contraindications or intolerance, most patients with AD would benefit from a trial of one or both of these medication classes,” said Dr. Tan. He added that it is equally important to wean off and discontinue these medications if there is intolerance or lack of a subjective or objective beneficial response.

Other medications are available for some of the most common behavioral problems associated with dementia, such as agitation, depression, and disorientation. Dr. Tan advised not to prescribe behavioral medications until nonpharmacologic interventions prove to be ineffective or impractical. Behavioral medications have many side effects, some of which are potentially serious, he said, so the risk-benefit ratio should be considered.

In his own practice, when nonpharmacologic strategies do not improve the behavioral symptoms of dementia, Dr. Tan said that, “in cases where a person is at risk of harm to themselves or others, a discussion with the patient and their caregivers about the pros and cons of medications to treat the behavior need to be had. Careful monitoring of the response and dose escalation or deprescribing when appropriate is important to keep in mind.”

Disease-modifying agents have recently provided new hope for AD treatment. Aducanumab and lecanemab, both monoclonal antibodies that target amyloids, are the first two drugs that received accelerated FDA approval for AD.

Although these monoclonal antibodies can help clear deposited amyloid plaques and show some benefit in slowing cognitive impairment in clinical trials, the real-world benefits were unclear enough for Medicare to limit coverage to people enrolled in approved studies to gather more data. Additionally, these agents can cause potentially amyloid-related imaging abnormalities, which may indicate edema, effusion, or microhemorrhage. Therefore, clinicians need to have a clear conversation of risks and benefits with patients and caregivers about these treatments.
 

Looking ahead

When asked about the most promising emerging technologies or techniques related to dementia diagnosis and management, Dr. Tan noted that multiple technology companies and start-ups are looking for new ways to detect dementia earlier or keep persons with dementia safe at home. Some devices deliver brain waves, computerized brain games or tests, automated pill dispensers, and fall monitors.

“Some of these are potentially helpful, but not every person with dementia will benefit. In addition, most of these technologies are out-of-pocket expenses for the patients and their families. It is important to know what is out there but also be cautious about outrageous claims,” he added.

Dr. Tan reported no relationships with entities whose primary business is producing, marketing, selling, reselling, or distributing health care products used by or on patients.

Advances in the understanding of neurobiological and neuro­psychiatric pathophysiology have opened new avenues of treatment for psychiatric patients. Historically, with a few exceptions, most psychiatric medications have been administered orally. However, many of the newer treatments require some form of specialized administration because they cannot be taken orally due to their chemical property (such as aducanumab); because there is the need to produce stable blood levels of the medication (such as brexanolone); because oral administration greatly diminished efficacy (such as oral vs IV magnesium or scopolamine), or because the treatment is focused on specific brain structures. This need for specialized administration has created a subspecialty called interventional psychiatry.

Part 1 of this 2-part article provides an overview of 1 type of interventional psychiatry: parenterally administered medications, including those administered via IV. We also describe 3 other interventional approaches to treatment: stellate ganglion blocks, glabellar botulinum toxin (BT) injections, and trigger point injections. In Part 2 we will review interventional approaches that involve neuromodulation.

Parenteral medications in psychiatry

In general, IV and IM medications can be more potent that oral medications due to their overall faster onset of action and higher blood concentrations. These more invasive forms of administration can have significant limitations, such as a risk of infection at the injection site, the need to be administered in a medical setting, additional time, and patient discomfort.

Table 1 lists short-acting injectable medications used in psychiatry, and Table 2 lists long-acting injectable medications. Parenteral administration of antipsychotics is performed to alleviate acute agitation or for chronic symptom control. These medications generally are not considered interventional treatments, but could be classified as such due to their invasive nature.¹ Furthermore, inhalable loxapine—which is indicated for managing acute agitation—requires a Risk Evaluation and Mitigation Strategy program consisting of 2 hours observation and monitoring of respiratory status.^2,3 Other indications for parenteral treatments include IM naltrexone extended release⁴ and subcutaneous injections of buprenorphine extended release⁵ and risperidone.⁶

IV administration

Most IV treatments described in this article are not FDA-approved for psychiatric treatment. Despite this, many interventional psychiatric treatments are part of clinical practice. IV infusion of ketamine is the most widely known and most researched of these. Table 3 lists other IV treatments that could be used as psychiatric treatment.

Ketamine

Since the early 1960s, ketamine has been used as a surgical anesthetic for animals. In the United States, it was approved for human surgical anesthesia in 1970. It was widely used during the Vietnam War due to its lack of inhibition of respiratory drive; medical staff first noticed an improvement in depressive symptoms and the resolution of suicidal ideation in patients who received ketamine. This led to further research on ketamine, particularly to determine its application in treatment-resistant depression (TRD) and other conditions.⁷ IV ketamine administration is most widely researched, but IM injections, intranasal sprays, and lozenges are also available. The dissociative properties of ketamine have led to its recreational use.⁸

Hypotheses for the mechanism of action of ketamine as an antidepressant include direct synaptic or extrasynaptic (GluN2B-selective), N-methyl-D-aspartate receptor (NMDAR) inhibition, selectively greater inhibition of NMDARs localized on GABAergic (gamma-aminobutyric acid) interneurons, and the role of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor activation. There are links between ketamine’s antidepressant actions and downstream mechanisms regulating synaptic plasticity, including brain-derived neurotrophic factor, eukaryotic elongation factor 2, mammalian target of rapamycin, and glycogen synthase kinase-3. Multiple other ketamine-associated mechanisms also have been described.^9,10 Action on the mu-opioid receptor is also known, possibly contributing to both antidepressant and anesthetic properties of ketamine.¹¹ Rapid onset of ketamine antidepressant action is especially valuable.¹²

Continue to: Ketamine is a schedule...

Ketamine is a schedule III medication with addictive properties. Delirium, panic attacks, hallucinations, nightmares, dysphoria, and paranoia may occur during and after use.¹³ Premedication with benzodiazepines, most notably lorazepam, is occasionally used to minimize ketamine’s adverse effects, but this generally is not recommended because doing so reduces ketamine’s antidepressant effects.¹⁴ Driving and operating heavy machinery is contraindicated after IV infusion. The usual protocol involves an IV infusion of ketamine 0.4 mg/kg to 1 mg/kg dosing over 1 hour. Doses between 0.4 mg/kg and 0.6 mg/kg are most common. Ketamine has a therapeutic window; doses >0.5 mg/kg are progressively less effective.¹⁵ Unlike the recommendation after esketamine administration, after receiving ketamine, patients remain in the care of their treatment team for <2 hours.

Esketamine, the S enantiomer of ketamine, was FDA-approved for TRD as an intranasal formulation. Esketamine is more commonly used than IV ketamine because it is FDA-approved and typically covered by insurance, but it may not be as effective.¹⁶ An economic analysis by Brendle et al¹⁷ suggested insurance companies would lower costs if they covered ketamine infusions vs intranasal esketamine.

Aducanumab and lecanemab

The most recent FDA-approved interventional agents are aducanumab and lecanemab, which are indicated for treating Alzheimer disease.^18,19 Both are human monoclonal antibodies that bind selectively and with high affinity to amyloid beta plaque aggregates and promote their removal by Fc receptor–mediated phagocytosis.²⁰

FDA approval of aducanumab and lecanemab was controversial. Initially, aducanumab’s safety monitoring board performed a futility analysis that suggested aducanumab was unlikely to separate from placebo, and the research was stopped.²¹ The manufacturer petitioned the FDA to consider the medication for accelerated approval on the basis of biomarker data showing that amyloid beta plaque aggregates become smaller. Current FDA approval is temporary to allow patients access to this potentially beneficial agent, but the manufacturer must supply clinical evidence that the reduction of amyloid beta plaques is associated with desirable changes in the course of Alzheimer disease, or risk losing the approval.

Lecanemab is also a human monoclonal antibody intended to remove amyloid beta plaques that was FDA-approved under the accelerated approval pathway.²² Unlike aducanumab, lecanemab demonstrated a statistically significant (although clinically imperceptible) reduction in the rate of cognitive decline; it did not show cognitive improvement.²³ Lecanemab also significantly reduced amyloid beta plaques.²³

Continue to: Aducanumab and lecanemab are generally...

Aducanumab and lecanemab are generally not covered by insurance and typically cost >$26,000 annually. Both are administered by IV infusion once a month. More monoclonal antibody medications for treating early Alzheimer disease are in the late stages of development, most notably donanebab.²⁴ Observations during clinical trials found that in the later stages of Alzheimer disease, forceful removal of plaques by the autoimmune process damages neurons, while in less dense deposits of early dementia such removal is not harmful to the cells and prevents amyloid buildup.

Brexanolone

Brexanolone is an aqueous formulation of allopregnanolone, a major metabolite of progesterone and a positive allosteric modulator of GABA-A receptors.²⁵ Its levels are maximal at the end of the third trimester of pregnancy and fall rapidly following delivery. Research showed a 3-day infusion was rapidly and significantly effective for treating postpartum depression²⁶ and brexanolone received FDA approval for this indication in March 2019.²⁷ However, various administrative, economic, insurance, and other hurdles make it difficult for patients to access this treatment. Despite its rapid onset of action (usually 48 hours), brexanolone takes an average of 15 days to go through the prior authorization process.²⁸ In addition to the need for prior authorization, the main impediment to the use of brexanolone is the 3-day infusion schedule, which greatly magnifies the cost but is partially circumvented by the availability of dedicated outpatient centers.

Magnesium

Magnesium is on the World Health Organization’s Model List of Essential Medicines.²⁹ There has been extensive research on the use of magnesium sulfate for psychiatric indications, especially for depression.³⁰ Magnesium functions similarly to calcium channel blockers by competitively blocking intracellular calcium channels, decreasing calcium availability, and inhibiting smooth muscle contractility.³¹ It also competes with calcium at the motor end plate, reducing excitation by inhibiting the release of acetylcholine.³² This property is used for high-dose IV magnesium treatment of impending preterm labor in obstetrics. Magnesium sulfate is the drug of choice in treating eclamptic seizures and preventing seizures in severe preeclampsia or gestational hypertension with severe features.³³ It is also used to treat torsade de pointes, severe asthma exacerbations, constipation, and barium poisoning.³⁴ Beneficial use in asthma treatment³⁵ and the treatment of migraine³⁶ have also been reported.

IV magnesium in myocardial infarction may be harmful,³⁷ though outside of acute cardiac events, magnesium is found to be safe.³⁸

Oral magnesium sulfate is a common over-the-counter anxiety remedy. As a general cell stabilizer (mediated by the reduction of intracellular calcium), magnesium is potentially beneficial outside of its muscle-relaxing properties, although muscle relaxing can benefit anxious patients. It is used to treat anxiety,³⁹ alcohol withdrawal,⁴⁰ and fear.⁴¹ Low magnesium blood levels are found in patients with depression, schizophrenia,⁴² and attention-deficit/hyperactivity disorder.⁴³ However, it is important to note that the therapeutic effect of magnesium when treating anxiety and headache is independent of preinfusion magnesium blood levels.⁴³

Continue to: The efficacy of oral magnesium...

The efficacy of oral magnesium is not robust. However, IV administration has a pronounced beneficial effect as an abortive and preventative treatment in many patients with anxiety.⁴⁴

IV administration of magnesium can produce adverse effects, including flushing, sweating, hypotension, depressed reflexes, flaccid paralysis, hypothermia, circulatory collapse, and cardiac and CNS depression. These complications are very rare and dose-dependent.⁴⁵ Magnesium is excreted by the kidneys, and dosing must be decreased in patients with kidney failure. The most common adverse effect is local burning along the vein upon infusion; small doses of IV lidocaine can remedy this. Hot flashes are also common.⁴⁵

Various dosing strategies are available. In patients with anxiety, application dosing is based on the recommended preeclampsia IV dose of 4 g diluted in 250 mL of 5% dextrose. Much higher doses may be used in obstetrics. Unlike in obstetrics, for psychiatric indications, magnesium is administered over 60 to 90 minutes. Heart monitoring is recommended.

Scopolamine

Scopolamine is primarily used to relieve nausea, vomiting, and dizziness associated with motion sickness and recovery from anesthesia. It is also used in ophthalmology and in patients with excessive sweating. In off-label and experimental applications, scopolamine has been used in patients with TRD.⁴⁶

Scopolamine is an anticholinergic medication. It is a nonselective antagonist at muscarinic receptors.⁴⁷ Tricyclic antidepressants (TCAs) possess strong anticholinergic function. Newer generations of antidepressants were designed specifically not to have this function because it was believed to be an unwanted and potentially dangerous adverse effect. However, data suggest that anticholinergic action is important in decreasing depressive symptoms. Several hypotheses of anticholinergic effects on depression have been published since the 1970s. They include the cholinergic-adrenergic hypothesis,⁴⁸ acetylcholine predominance relative to adrenergic action hypothesis,⁴⁹ and insecticide poisoning observations.⁵⁰ Centrally acting physostigmine (but not peripherally acting neostigmine) was reported to control mania.^48,51 A genetic connection between the M2acetylcholine receptor in patients with major depressive disorder (MDD) and alcohol use disorder is also suggestive.⁵²

Continue to: Multiple animal studies show...

Multiple animal studies show direct improvement in mobility and a decrease in despair upon introducing anticholinergic substances.^53-55 The cholinergic theory of depression has been studied in several controlled clinical human studies.^56,57 Use of a short-acting anticholinergic glycopyrrolate during electroconvulsive therapy (ECT) may contribute to the procedure’s efficacy.

Human research shows scopolamine has a higher efficacy as an antidepressant and anti-anxiety medication in women than in men,⁵⁸ possibly because estrogen increases the activity of choline acetyltransferase and release of acetylcholine.^59,60 M2receptors mediate estrogen influence on the NMDAR, which may explain the anticholinergic effects of depression treatments in women.⁶¹

Another proposed mechanism of action of scopolamine is a potent inhibition of the NMDAR.⁶² Rapid treatments of depression may be based on this mechanism. Examples of such treatments include IV ketamine and sleep deprivation.⁶³ IV scopolamine shows potency in treating MDD and bipolar depression. This treatment should be reserved for patients who do not respond to or are not candidates for other usual treatment modalities of MDD and for the most severe cases. Scopolamine is 30 times more potent than amitriptyline in anticholinergic effect and reportedly produces sustained improvement in MDD.⁶⁴

Scopolamine has no black-box warnings. It has not been studied in pregnant women and is not recommended for use during pregnancy. Due to possible negative cardiovascular effects, a normal electrocardiogram is required before the start of treatment. Exercise caution in patients with glaucoma, benign prostatic enlargement, gastroparesis, unstable cardiovascular status, or severe renal impairment.

Treatment with scopolamine is not indicated for patients with myasthenia gravis, psychosis, or seizures. Patients must be off potassium for 3 days before beginning scopolamine treatment. Patients should consult with their cardiologist before having a scopolamine infusion. Adverse reactions may include psychosis, tachycardia, seizures, paralytic ileus, and glaucoma exacerbation. The most common adverse effects of scopolamine infusion treatment include drowsiness, dry mouth, blurred vision, lightheadedness, and dizziness. Due to possible drowsiness, operating motor vehicles or heavy machinery must be avoided on the day of treatment.⁶⁵ Overall, the adverse effects of scopolamine are preventable and manageable, and its antidepressant efficacy is noteworthy.⁶⁶

Continue to: Treatment typically consists of 3 consecutive infusions...

Treatment typically consists of 3 consecutive infusions of 4 mcg/kg separated by 3 to 5 days.⁵⁶ It is possible to have a longer treatment course if the patient experiences only partial improvement. Repeated courses or maintenance treatment (similar to ECT maintenance) are utilized in some patients if indicated. Cardiac monitoring is mandatory.

Clomipramine

Clomipramine, a TCA, acts as a preferential inhibitor of 5-hydroxytryptamine uptake and has proven effective in managing depression, TRD, and obsessive-compulsive disorder (OCD).⁶⁷ Although this medication has reported treatment benefits for patients with phobia, panic disorder,¹⁵ chronic pain,⁶⁸ Tourette syndrome,⁶⁹ premature ejaculation, anorexia nervosa,⁷⁰ cataplexy,⁴⁹ and enuresis,⁷¹ it is FDA-approved only for the treatment of OCD.⁷² Clomipramine may also be beneficial for pain and headache, possibly because of its anti-inflammatory action.⁷³ The anticholinergic effects of clomipramine may add to its efficacy in depression.

The pathophysiology of MDD is connected to hyperactivity of the HPA axis and elevated cortisol levels. Higher clomipramine plasma levels show a linear correlation with lower cortisol secretion and levels, possibly aiding in the treatment of MDD and anxiety.⁷⁴ The higher the blood level, the more pronounced clomipramine’s therapeutic effect across multiple domains.⁷⁵

IV infusion of clomipramine produces the highest concentration in the shortest time, but overall, research does not necessarily support increased efficacy of IV over oral administration. There is evidence suggesting that subgroups of patients with severe, treatment-refractory OCD may benefit from IV agents and research suggests a faster onset of action.⁷⁶ Faster onset of symptom relief is the basis for IV clomipramine use. In patients with OCD, it can take several months for oral medications to produce therapeutic benefits; not all patients can tolerate this. In such scenarios, IV administration may be considered, though it is not appropriate for routine use until more research is available. Patients with treatment-resistant OCD who have exhausted other means of symptom relief may also be candidates for IV treatment.

The adverse effects of IV clomipramine are no different from oral use, though they may be more pronounced. A pretreatment cardiac exam is desirable because clomipramine, like other TCAs, may be cardiotoxic. The anticholinergic adverse effects of TCAs are well known to clinicians⁷⁷ and partially explained in the scopolamine section of this article. It is not advisable to combine clomipramine with other TCAs or serotonin reuptake inhibitors. Clomipramine also should not be combined with monoamine oxidase inhibitors, though such a combination was reported in medical literature.⁷⁸ Combination with antiarrhythmics such as lidocaine or opioids such as fentanyl or and tramadol is highly discouraged (fentanyl and tramadol also have serotonergic effects).⁷⁹

Continue to: Clomipramine for IV use is not commercially available...

Clomipramine for IV use is not commercially available and must be sterilely compounded. The usual course of treatment is a series of 3 infusions: 150 mg on Day 1, 200 mg on Day 2 or Day 3, and 250 mg on Day 3, Day 4, or Day 5, depending on tolerability. A protocol with a 50 mg/d starting dose and titration up to a maximum dose of 225 mg/d over 5 to 7 days has been suggested for inpatient settings.⁶⁷ Titration to 250 mg is more common.⁸⁰

A longer series may be performed, but this increases the likelihood of adverse effects. Booster and maintenance treatments are also completed when required. Cardiac monitoring is mandatory.

Vortioxetine and citalopram

IV treatment of depression with vortioxetine and citalopram has been explored but has not yet taken hold in clinical psychiatry.^81,82

Injections and blocks

Three interventional approaches to treatment that possess psychotherapeutic potential include stellate ganglion blocks (SGBs), glabellar BT injections, and trigger point injections (TPIs). None of these are FDA-approved for psychiatric treatment.

Stellate ganglion blocks

The sympathetic nervous system is involved in autonomic hyperarousal and is at the core of posttraumatic symptomatology.⁸³ Insomnia, anxiety, irritability, hypervigilance, and other excitatory CNS events are connected to the sympathetic nervous system and amygdala activation is commonly observed in those exposed to extreme stress or traumatic events.⁸⁴

Continue to: SGBs were first performed 100 years ago...

SGBs were first performed 100 years ago and reported to have beneficial psychiatric effects at the end of the 1940s. In 1998 in Finland, improvement of posttraumatic stress disorder (PTSD) symptoms was observed accidentally via thoracic level spine blocks.⁸⁵ In 2006, cervical level sympathetic blocks were shown to be effective for PTSD symptom control.⁸⁶ By the end of 2010, Veterans Administration hospitals adopted SGBs to treat veterans with PTSD.^87,88 The first multisite, randomized clinical trial of SGB for PTSD confirmed multiple previous reports of treatment efficacy. Specifically, 2 SGB treatments 2 weeks apart effectively reduced total symptom severity scores over 8 weeks.⁸⁷

Since the stellate ganglion is connected to the amygdala, SGB has also been assessed for treating anxiety and depression.^89,90 Outside of PTSD, SGBs are used to treat complex regional pain syndrome,⁹¹ phantom limb pain, trigeminal neuralgia,⁹² intractable angina,⁹³ and postherpetic neuralgia in the head, neck, upper chest, or arms.⁹⁴ The procedure consists of an injection of a local anesthetic through a 25-gauge needle into the stellate sympathetic ganglion at the C6 or C7 vertebral levels. An injection into C6 is considered safer because of specific cervical spine anatomy. Ideally, fluoroscopic guidance or ultrasound is used to guide needle insertion.⁹⁵

A severe drop in blood pressure may be associated with SGBs and is mitigated by IV hydration. Other adverse effects include red eyes, drooping of the eyelids, nasal congestion, hoarseness, difficulty swallowing, a sensation of a “lump” in the throat, and a sensation of warmth or tingling in the arm or hand. Bilateral SGB is contraindicated due to the danger of respiratory arrest.⁹⁶

Glabellar BT injections

OnabotulinumtoxinA (BT) injection was first approved for therapeutic use in 1989 for eye muscle disorders such as strabismus⁹⁷ and blepharospasm.⁹⁸ It was later approved for several other indications, including cosmetic use, hyperhidrosis, migraine prevention, neurogenic bladder disorder, overactive bladder, urinary incontinence, and spasticity.^99-104 BT is used off-label for achalasia and sialorrhea.^105,106 Its mechanism of action is primarily attributed to muscle paralysis by blocking presynaptic acetylcholine release into neuromuscular junctions.¹⁰⁷

Facial BT injections are usually administered for cosmetic purposes, but smoothing forehead wrinkles and frown lines (the glabellar region of the face) both have antidepressant effects.¹⁰⁸ BT injections into the glabellar region also demonstrate antidepressant effects, particularly in patients with comorbid migraines and MDD.¹⁰⁹ Early case observations supported the independent benefit of the toxin on MDD when the toxin was injected into the glabellar region.^110,111 The most frequent protocol involves injections in the procerus and corrugator muscles.

Continue to: The facial feedback/emotional proprioception hypothesis...

The facial feedback/emotional proprioception hypothesis has dominated thinking about the mood-improving effects of BT. The theory is that blocking muscular expression of sadness (especially in the face) interrupts the experience of sadness; therefore, depression subsides.^112,113 However, BT injections in the muscles involved in the smile and an expression of positive emotions (lateral part of the musculus orbicularis oculi) have been associated with increased MDD scores.¹¹⁴ Thus, the mechanism clearly involves more than the cosmetic effect, since facial muscle injections in rats also have antidepressant effects.¹¹⁵

The use of progressive muscle relaxation is well-established in psychiatric treatment. The investigated conditions of increased muscle tone, especially torticollis and blepharospasm, are associated with MDD, and it may be speculated that proprioceptive feedback from the affected muscles may be causally involved in this association.^116-118 Activity of the corrugator muscle has been positively associated with increased amygdala activity.¹¹⁹ This suggests a potential similar mechanism to that hypothesized for SGB.

Alternatively, BT is commonly used to treat chronic conditions that may contribute to depression; its success in relieving the underlying problem may indirectly relieve MDD. Thus, in a postmarketing safety evaluation of BT, MDD was demonstrated 40% to 88% less often by patients treated with BT for 6 of the 8 conditions and injection sites, such as in spasms and spasticity of arms and legs, torticollis and neck pain, and axilla and palm injections for hyperhidrosis. In a parotid and submandibular glands BT injection subcohort, no patients experienced depressive symptoms.¹²⁰

Medicinal BT is generally considered safe. The most common adverse effects are hypersensitivity, injection site reactions, and other adverse effects specific to the injection site.¹²¹ Additionally, the cosmetic effects are transient, given the nature of the medication.

Trigger point injections

TPIs in the neck and shoulders are frequently used to treat tension headaches and various referred pain locations in the face and arms. Tension and depression frequently overlap in clinical practice.¹²² Relieving muscle tension (with resulting trigger points) improves muscle function and mood.

Continue to: The higher the number of active...

The higher the number of active trigger points (TPs), the greater the physical burden of headache and the higher the anxiety level. Gender differences in TP prevalence and TPI efficacy have been described in the literature. For example, the number of active TPs seems directly associated with anxiety levels in women but not in men.¹²³ Although TPs appear to be more closely associated with anxiety than depression,¹²⁴ depression associated with muscle tension does improve with TPIs. European studies have demonstrated a decrease in scores on the Hamilton Depression Rating Scale and Hamilton Anxiety Rating Scale following TPI treatment.¹²⁵ The effect may be indirect, as when a patient’s pain is relieved, sleep and other psychiatric symptoms improve.¹²⁶

A randomized controlled trial by Castro Sánchez et al¹²⁷ demonstrated that dry needling therapy in patients with fibromyalgia syndrome (FMS) showed improvements in pain pressure thresholds, body pain, vitality, and social function, as well as total FMS symptoms, quality of sleep, anxiety, hospital anxiety and depression, general pain intensity, and fatigue.

Myofascial pain syndrome, catastrophizing, and muscle tension are common in patients with depression, anxiety, and somatization. Local TPI therapy aimed at inactivating pain generators is supported by moderate quality evidence. All manner of therapies have been described, including injection of saline, corticosteroids, local anesthetic agents, and dry needling. BT injections in chronic TPs are also practiced, though no specific injection therapy has been reliably shown to be more advantageous than another. The benefits of TPIs may be derived from the needle itself rather than from any specific substance injected. Stimulation of a local twitch response with direct needling of the TP appears of importance. There is no established consensus regarding the number of injection points, frequency of administration, and volume or type of injectate.¹²⁸

Adverse effects of TPIs relate to the nature of the invasive therapy, with the risk of tissue damage and bleeding. Pneumothorax risk is present with needle insertion at the neck and thorax.¹²⁹ Patients with diabetes may experience variations in blood sugar control if steroids are used.

Bottom Line

Interventional treatment modalities that may have a role in psychiatric treatment include IV administration of ketamine, aducanumab, lecanemab, brexanolone, magnesium, scopolamine, and clomipramine. Other interventional approaches include stellate ganglion blocks, glabellar botulinum toxin injections, and trigger point injections.

Related Resources

• Dokucu ME, Janicak PG. Nontraditional therapies for treatment-resistant depression. Current Psychiatry. 2021; 20(9):38-43,49. doi:10.12788/cp.0166
• Kim J, Khoury R, Grossberg GT. Botulinum toxin: emerging psychiatric indications. Current Psychiatry. 2018;17(12):8-18.

Drug Brand Names

Aducanumab • Aduhelm
Aripiprazole • Abilify
Aripiprazole lauroxil • Aristada
Brexanolone • Zulresso
Buprenorphine • Sublocade
Citalopram • Celexa
Clomipramine • Anafranil
Diazepam • Valium
Droperidol • Inapsine
Esketamine • Spravato
Fentanyl • Actiq
Fluphenazine decanoate • Modecate
Fluphenazine hydrochloride • Prolixin
Haloperidol decanoate • Haldol decanoate
Haloperidol lactate • Haldol
Ketamine • Ketalar
Lecanemab • Leqembi
Lidocaine • Xylocaine
Lorazepam • Ativan
Loxapine inhaled • Adasuve
Naltrexone • Vivitrol
Magnesium sulfate • Sulfamag
Midazolam • Versed
Olanzapine • Zyprexa
OnabotulinumtoxinA injection • Botox
Paliperidone • Invega Hafyera, Invega Sustenna, Invega Trinza
Rapamycin • Rapamune, Sirolimus
Risperidone • Perseris
Risperidone microspheres • Risperdal Consta, Rykindo
Scopolamine • Hyoscine
Tramadol • Conzip
Vortioxetine • Trintellix
Ziprasidone • Geodon

Advances in the understanding of neurobiological and neuro­psychiatric pathophysiology have opened new avenues of treatment for psychiatric patients. Historically, with a few exceptions, most psychiatric medications have been administered orally. However, many of the newer treatments require some form of specialized administration because they cannot be taken orally due to their chemical property (such as aducanumab); because there is the need to produce stable blood levels of the medication (such as brexanolone); because oral administration greatly diminished efficacy (such as oral vs IV magnesium or scopolamine), or because the treatment is focused on specific brain structures. This need for specialized administration has created a subspecialty called interventional psychiatry.

Part 1 of this 2-part article provides an overview of 1 type of interventional psychiatry: parenterally administered medications, including those administered via IV. We also describe 3 other interventional approaches to treatment: stellate ganglion blocks, glabellar botulinum toxin (BT) injections, and trigger point injections. In Part 2 we will review interventional approaches that involve neuromodulation.

Parenteral medications in psychiatry

In general, IV and IM medications can be more potent that oral medications due to their overall faster onset of action and higher blood concentrations. These more invasive forms of administration can have significant limitations, such as a risk of infection at the injection site, the need to be administered in a medical setting, additional time, and patient discomfort.

Table 1 lists short-acting injectable medications used in psychiatry, and Table 2 lists long-acting injectable medications. Parenteral administration of antipsychotics is performed to alleviate acute agitation or for chronic symptom control. These medications generally are not considered interventional treatments, but could be classified as such due to their invasive nature.¹ Furthermore, inhalable loxapine—which is indicated for managing acute agitation—requires a Risk Evaluation and Mitigation Strategy program consisting of 2 hours observation and monitoring of respiratory status.^2,3 Other indications for parenteral treatments include IM naltrexone extended release⁴ and subcutaneous injections of buprenorphine extended release⁵ and risperidone.⁶

IV administration

Most IV treatments described in this article are not FDA-approved for psychiatric treatment. Despite this, many interventional psychiatric treatments are part of clinical practice. IV infusion of ketamine is the most widely known and most researched of these. Table 3 lists other IV treatments that could be used as psychiatric treatment.

Ketamine

Since the early 1960s, ketamine has been used as a surgical anesthetic for animals. In the United States, it was approved for human surgical anesthesia in 1970. It was widely used during the Vietnam War due to its lack of inhibition of respiratory drive; medical staff first noticed an improvement in depressive symptoms and the resolution of suicidal ideation in patients who received ketamine. This led to further research on ketamine, particularly to determine its application in treatment-resistant depression (TRD) and other conditions.⁷ IV ketamine administration is most widely researched, but IM injections, intranasal sprays, and lozenges are also available. The dissociative properties of ketamine have led to its recreational use.⁸

Hypotheses for the mechanism of action of ketamine as an antidepressant include direct synaptic or extrasynaptic (GluN2B-selective), N-methyl-D-aspartate receptor (NMDAR) inhibition, selectively greater inhibition of NMDARs localized on GABAergic (gamma-aminobutyric acid) interneurons, and the role of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor activation. There are links between ketamine’s antidepressant actions and downstream mechanisms regulating synaptic plasticity, including brain-derived neurotrophic factor, eukaryotic elongation factor 2, mammalian target of rapamycin, and glycogen synthase kinase-3. Multiple other ketamine-associated mechanisms also have been described.^9,10 Action on the mu-opioid receptor is also known, possibly contributing to both antidepressant and anesthetic properties of ketamine.¹¹ Rapid onset of ketamine antidepressant action is especially valuable.¹²

Continue to: Ketamine is a schedule...

Ketamine is a schedule III medication with addictive properties. Delirium, panic attacks, hallucinations, nightmares, dysphoria, and paranoia may occur during and after use.¹³ Premedication with benzodiazepines, most notably lorazepam, is occasionally used to minimize ketamine’s adverse effects, but this generally is not recommended because doing so reduces ketamine’s antidepressant effects.¹⁴ Driving and operating heavy machinery is contraindicated after IV infusion. The usual protocol involves an IV infusion of ketamine 0.4 mg/kg to 1 mg/kg dosing over 1 hour. Doses between 0.4 mg/kg and 0.6 mg/kg are most common. Ketamine has a therapeutic window; doses >0.5 mg/kg are progressively less effective.¹⁵ Unlike the recommendation after esketamine administration, after receiving ketamine, patients remain in the care of their treatment team for <2 hours.

Esketamine, the S enantiomer of ketamine, was FDA-approved for TRD as an intranasal formulation. Esketamine is more commonly used than IV ketamine because it is FDA-approved and typically covered by insurance, but it may not be as effective.¹⁶ An economic analysis by Brendle et al¹⁷ suggested insurance companies would lower costs if they covered ketamine infusions vs intranasal esketamine.

Aducanumab and lecanemab

The most recent FDA-approved interventional agents are aducanumab and lecanemab, which are indicated for treating Alzheimer disease.^18,19 Both are human monoclonal antibodies that bind selectively and with high affinity to amyloid beta plaque aggregates and promote their removal by Fc receptor–mediated phagocytosis.²⁰

FDA approval of aducanumab and lecanemab was controversial. Initially, aducanumab’s safety monitoring board performed a futility analysis that suggested aducanumab was unlikely to separate from placebo, and the research was stopped.²¹ The manufacturer petitioned the FDA to consider the medication for accelerated approval on the basis of biomarker data showing that amyloid beta plaque aggregates become smaller. Current FDA approval is temporary to allow patients access to this potentially beneficial agent, but the manufacturer must supply clinical evidence that the reduction of amyloid beta plaques is associated with desirable changes in the course of Alzheimer disease, or risk losing the approval.

Lecanemab is also a human monoclonal antibody intended to remove amyloid beta plaques that was FDA-approved under the accelerated approval pathway.²² Unlike aducanumab, lecanemab demonstrated a statistically significant (although clinically imperceptible) reduction in the rate of cognitive decline; it did not show cognitive improvement.²³ Lecanemab also significantly reduced amyloid beta plaques.²³

Continue to: Aducanumab and lecanemab are generally...

Aducanumab and lecanemab are generally not covered by insurance and typically cost >$26,000 annually. Both are administered by IV infusion once a month. More monoclonal antibody medications for treating early Alzheimer disease are in the late stages of development, most notably donanebab.²⁴ Observations during clinical trials found that in the later stages of Alzheimer disease, forceful removal of plaques by the autoimmune process damages neurons, while in less dense deposits of early dementia such removal is not harmful to the cells and prevents amyloid buildup.

Brexanolone

Brexanolone is an aqueous formulation of allopregnanolone, a major metabolite of progesterone and a positive allosteric modulator of GABA-A receptors.²⁵ Its levels are maximal at the end of the third trimester of pregnancy and fall rapidly following delivery. Research showed a 3-day infusion was rapidly and significantly effective for treating postpartum depression²⁶ and brexanolone received FDA approval for this indication in March 2019.²⁷ However, various administrative, economic, insurance, and other hurdles make it difficult for patients to access this treatment. Despite its rapid onset of action (usually 48 hours), brexanolone takes an average of 15 days to go through the prior authorization process.²⁸ In addition to the need for prior authorization, the main impediment to the use of brexanolone is the 3-day infusion schedule, which greatly magnifies the cost but is partially circumvented by the availability of dedicated outpatient centers.

Magnesium

Magnesium is on the World Health Organization’s Model List of Essential Medicines.²⁹ There has been extensive research on the use of magnesium sulfate for psychiatric indications, especially for depression.³⁰ Magnesium functions similarly to calcium channel blockers by competitively blocking intracellular calcium channels, decreasing calcium availability, and inhibiting smooth muscle contractility.³¹ It also competes with calcium at the motor end plate, reducing excitation by inhibiting the release of acetylcholine.³² This property is used for high-dose IV magnesium treatment of impending preterm labor in obstetrics. Magnesium sulfate is the drug of choice in treating eclamptic seizures and preventing seizures in severe preeclampsia or gestational hypertension with severe features.³³ It is also used to treat torsade de pointes, severe asthma exacerbations, constipation, and barium poisoning.³⁴ Beneficial use in asthma treatment³⁵ and the treatment of migraine³⁶ have also been reported.

IV magnesium in myocardial infarction may be harmful,³⁷ though outside of acute cardiac events, magnesium is found to be safe.³⁸

Oral magnesium sulfate is a common over-the-counter anxiety remedy. As a general cell stabilizer (mediated by the reduction of intracellular calcium), magnesium is potentially beneficial outside of its muscle-relaxing properties, although muscle relaxing can benefit anxious patients. It is used to treat anxiety,³⁹ alcohol withdrawal,⁴⁰ and fear.⁴¹ Low magnesium blood levels are found in patients with depression, schizophrenia,⁴² and attention-deficit/hyperactivity disorder.⁴³ However, it is important to note that the therapeutic effect of magnesium when treating anxiety and headache is independent of preinfusion magnesium blood levels.⁴³

Continue to: The efficacy of oral magnesium...

The efficacy of oral magnesium is not robust. However, IV administration has a pronounced beneficial effect as an abortive and preventative treatment in many patients with anxiety.⁴⁴

IV administration of magnesium can produce adverse effects, including flushing, sweating, hypotension, depressed reflexes, flaccid paralysis, hypothermia, circulatory collapse, and cardiac and CNS depression. These complications are very rare and dose-dependent.⁴⁵ Magnesium is excreted by the kidneys, and dosing must be decreased in patients with kidney failure. The most common adverse effect is local burning along the vein upon infusion; small doses of IV lidocaine can remedy this. Hot flashes are also common.⁴⁵

Various dosing strategies are available. In patients with anxiety, application dosing is based on the recommended preeclampsia IV dose of 4 g diluted in 250 mL of 5% dextrose. Much higher doses may be used in obstetrics. Unlike in obstetrics, for psychiatric indications, magnesium is administered over 60 to 90 minutes. Heart monitoring is recommended.

Scopolamine

Scopolamine is primarily used to relieve nausea, vomiting, and dizziness associated with motion sickness and recovery from anesthesia. It is also used in ophthalmology and in patients with excessive sweating. In off-label and experimental applications, scopolamine has been used in patients with TRD.⁴⁶

Scopolamine is an anticholinergic medication. It is a nonselective antagonist at muscarinic receptors.⁴⁷ Tricyclic antidepressants (TCAs) possess strong anticholinergic function. Newer generations of antidepressants were designed specifically not to have this function because it was believed to be an unwanted and potentially dangerous adverse effect. However, data suggest that anticholinergic action is important in decreasing depressive symptoms. Several hypotheses of anticholinergic effects on depression have been published since the 1970s. They include the cholinergic-adrenergic hypothesis,⁴⁸ acetylcholine predominance relative to adrenergic action hypothesis,⁴⁹ and insecticide poisoning observations.⁵⁰ Centrally acting physostigmine (but not peripherally acting neostigmine) was reported to control mania.^48,51 A genetic connection between the M2acetylcholine receptor in patients with major depressive disorder (MDD) and alcohol use disorder is also suggestive.⁵²

Continue to: Multiple animal studies show...

Multiple animal studies show direct improvement in mobility and a decrease in despair upon introducing anticholinergic substances.^53-55 The cholinergic theory of depression has been studied in several controlled clinical human studies.^56,57 Use of a short-acting anticholinergic glycopyrrolate during electroconvulsive therapy (ECT) may contribute to the procedure’s efficacy.

Human research shows scopolamine has a higher efficacy as an antidepressant and anti-anxiety medication in women than in men,⁵⁸ possibly because estrogen increases the activity of choline acetyltransferase and release of acetylcholine.^59,60 M2receptors mediate estrogen influence on the NMDAR, which may explain the anticholinergic effects of depression treatments in women.⁶¹

Another proposed mechanism of action of scopolamine is a potent inhibition of the NMDAR.⁶² Rapid treatments of depression may be based on this mechanism. Examples of such treatments include IV ketamine and sleep deprivation.⁶³ IV scopolamine shows potency in treating MDD and bipolar depression. This treatment should be reserved for patients who do not respond to or are not candidates for other usual treatment modalities of MDD and for the most severe cases. Scopolamine is 30 times more potent than amitriptyline in anticholinergic effect and reportedly produces sustained improvement in MDD.⁶⁴

Scopolamine has no black-box warnings. It has not been studied in pregnant women and is not recommended for use during pregnancy. Due to possible negative cardiovascular effects, a normal electrocardiogram is required before the start of treatment. Exercise caution in patients with glaucoma, benign prostatic enlargement, gastroparesis, unstable cardiovascular status, or severe renal impairment.

Treatment with scopolamine is not indicated for patients with myasthenia gravis, psychosis, or seizures. Patients must be off potassium for 3 days before beginning scopolamine treatment. Patients should consult with their cardiologist before having a scopolamine infusion. Adverse reactions may include psychosis, tachycardia, seizures, paralytic ileus, and glaucoma exacerbation. The most common adverse effects of scopolamine infusion treatment include drowsiness, dry mouth, blurred vision, lightheadedness, and dizziness. Due to possible drowsiness, operating motor vehicles or heavy machinery must be avoided on the day of treatment.⁶⁵ Overall, the adverse effects of scopolamine are preventable and manageable, and its antidepressant efficacy is noteworthy.⁶⁶

Continue to: Treatment typically consists of 3 consecutive infusions...

Treatment typically consists of 3 consecutive infusions of 4 mcg/kg separated by 3 to 5 days.⁵⁶ It is possible to have a longer treatment course if the patient experiences only partial improvement. Repeated courses or maintenance treatment (similar to ECT maintenance) are utilized in some patients if indicated. Cardiac monitoring is mandatory.

Clomipramine

Clomipramine, a TCA, acts as a preferential inhibitor of 5-hydroxytryptamine uptake and has proven effective in managing depression, TRD, and obsessive-compulsive disorder (OCD).⁶⁷ Although this medication has reported treatment benefits for patients with phobia, panic disorder,¹⁵ chronic pain,⁶⁸ Tourette syndrome,⁶⁹ premature ejaculation, anorexia nervosa,⁷⁰ cataplexy,⁴⁹ and enuresis,⁷¹ it is FDA-approved only for the treatment of OCD.⁷² Clomipramine may also be beneficial for pain and headache, possibly because of its anti-inflammatory action.⁷³ The anticholinergic effects of clomipramine may add to its efficacy in depression.

The pathophysiology of MDD is connected to hyperactivity of the HPA axis and elevated cortisol levels. Higher clomipramine plasma levels show a linear correlation with lower cortisol secretion and levels, possibly aiding in the treatment of MDD and anxiety.⁷⁴ The higher the blood level, the more pronounced clomipramine’s therapeutic effect across multiple domains.⁷⁵

IV infusion of clomipramine produces the highest concentration in the shortest time, but overall, research does not necessarily support increased efficacy of IV over oral administration. There is evidence suggesting that subgroups of patients with severe, treatment-refractory OCD may benefit from IV agents and research suggests a faster onset of action.⁷⁶ Faster onset of symptom relief is the basis for IV clomipramine use. In patients with OCD, it can take several months for oral medications to produce therapeutic benefits; not all patients can tolerate this. In such scenarios, IV administration may be considered, though it is not appropriate for routine use until more research is available. Patients with treatment-resistant OCD who have exhausted other means of symptom relief may also be candidates for IV treatment.

The adverse effects of IV clomipramine are no different from oral use, though they may be more pronounced. A pretreatment cardiac exam is desirable because clomipramine, like other TCAs, may be cardiotoxic. The anticholinergic adverse effects of TCAs are well known to clinicians⁷⁷ and partially explained in the scopolamine section of this article. It is not advisable to combine clomipramine with other TCAs or serotonin reuptake inhibitors. Clomipramine also should not be combined with monoamine oxidase inhibitors, though such a combination was reported in medical literature.⁷⁸ Combination with antiarrhythmics such as lidocaine or opioids such as fentanyl or and tramadol is highly discouraged (fentanyl and tramadol also have serotonergic effects).⁷⁹

Continue to: Clomipramine for IV use is not commercially available...

Clomipramine for IV use is not commercially available and must be sterilely compounded. The usual course of treatment is a series of 3 infusions: 150 mg on Day 1, 200 mg on Day 2 or Day 3, and 250 mg on Day 3, Day 4, or Day 5, depending on tolerability. A protocol with a 50 mg/d starting dose and titration up to a maximum dose of 225 mg/d over 5 to 7 days has been suggested for inpatient settings.⁶⁷ Titration to 250 mg is more common.⁸⁰

A longer series may be performed, but this increases the likelihood of adverse effects. Booster and maintenance treatments are also completed when required. Cardiac monitoring is mandatory.

Vortioxetine and citalopram

IV treatment of depression with vortioxetine and citalopram has been explored but has not yet taken hold in clinical psychiatry.^81,82

Injections and blocks

Three interventional approaches to treatment that possess psychotherapeutic potential include stellate ganglion blocks (SGBs), glabellar BT injections, and trigger point injections (TPIs). None of these are FDA-approved for psychiatric treatment.

Stellate ganglion blocks

The sympathetic nervous system is involved in autonomic hyperarousal and is at the core of posttraumatic symptomatology.⁸³ Insomnia, anxiety, irritability, hypervigilance, and other excitatory CNS events are connected to the sympathetic nervous system and amygdala activation is commonly observed in those exposed to extreme stress or traumatic events.⁸⁴

Continue to: SGBs were first performed 100 years ago...

SGBs were first performed 100 years ago and reported to have beneficial psychiatric effects at the end of the 1940s. In 1998 in Finland, improvement of posttraumatic stress disorder (PTSD) symptoms was observed accidentally via thoracic level spine blocks.⁸⁵ In 2006, cervical level sympathetic blocks were shown to be effective for PTSD symptom control.⁸⁶ By the end of 2010, Veterans Administration hospitals adopted SGBs to treat veterans with PTSD.^87,88 The first multisite, randomized clinical trial of SGB for PTSD confirmed multiple previous reports of treatment efficacy. Specifically, 2 SGB treatments 2 weeks apart effectively reduced total symptom severity scores over 8 weeks.⁸⁷

Since the stellate ganglion is connected to the amygdala, SGB has also been assessed for treating anxiety and depression.^89,90 Outside of PTSD, SGBs are used to treat complex regional pain syndrome,⁹¹ phantom limb pain, trigeminal neuralgia,⁹² intractable angina,⁹³ and postherpetic neuralgia in the head, neck, upper chest, or arms.⁹⁴ The procedure consists of an injection of a local anesthetic through a 25-gauge needle into the stellate sympathetic ganglion at the C6 or C7 vertebral levels. An injection into C6 is considered safer because of specific cervical spine anatomy. Ideally, fluoroscopic guidance or ultrasound is used to guide needle insertion.⁹⁵

A severe drop in blood pressure may be associated with SGBs and is mitigated by IV hydration. Other adverse effects include red eyes, drooping of the eyelids, nasal congestion, hoarseness, difficulty swallowing, a sensation of a “lump” in the throat, and a sensation of warmth or tingling in the arm or hand. Bilateral SGB is contraindicated due to the danger of respiratory arrest.⁹⁶

Glabellar BT injections

OnabotulinumtoxinA (BT) injection was first approved for therapeutic use in 1989 for eye muscle disorders such as strabismus⁹⁷ and blepharospasm.⁹⁸ It was later approved for several other indications, including cosmetic use, hyperhidrosis, migraine prevention, neurogenic bladder disorder, overactive bladder, urinary incontinence, and spasticity.^99-104 BT is used off-label for achalasia and sialorrhea.^105,106 Its mechanism of action is primarily attributed to muscle paralysis by blocking presynaptic acetylcholine release into neuromuscular junctions.¹⁰⁷

Facial BT injections are usually administered for cosmetic purposes, but smoothing forehead wrinkles and frown lines (the glabellar region of the face) both have antidepressant effects.¹⁰⁸ BT injections into the glabellar region also demonstrate antidepressant effects, particularly in patients with comorbid migraines and MDD.¹⁰⁹ Early case observations supported the independent benefit of the toxin on MDD when the toxin was injected into the glabellar region.^110,111 The most frequent protocol involves injections in the procerus and corrugator muscles.

Continue to: The facial feedback/emotional proprioception hypothesis...

The facial feedback/emotional proprioception hypothesis has dominated thinking about the mood-improving effects of BT. The theory is that blocking muscular expression of sadness (especially in the face) interrupts the experience of sadness; therefore, depression subsides.^112,113 However, BT injections in the muscles involved in the smile and an expression of positive emotions (lateral part of the musculus orbicularis oculi) have been associated with increased MDD scores.¹¹⁴ Thus, the mechanism clearly involves more than the cosmetic effect, since facial muscle injections in rats also have antidepressant effects.¹¹⁵

The use of progressive muscle relaxation is well-established in psychiatric treatment. The investigated conditions of increased muscle tone, especially torticollis and blepharospasm, are associated with MDD, and it may be speculated that proprioceptive feedback from the affected muscles may be causally involved in this association.^116-118 Activity of the corrugator muscle has been positively associated with increased amygdala activity.¹¹⁹ This suggests a potential similar mechanism to that hypothesized for SGB.

Alternatively, BT is commonly used to treat chronic conditions that may contribute to depression; its success in relieving the underlying problem may indirectly relieve MDD. Thus, in a postmarketing safety evaluation of BT, MDD was demonstrated 40% to 88% less often by patients treated with BT for 6 of the 8 conditions and injection sites, such as in spasms and spasticity of arms and legs, torticollis and neck pain, and axilla and palm injections for hyperhidrosis. In a parotid and submandibular glands BT injection subcohort, no patients experienced depressive symptoms.¹²⁰

Medicinal BT is generally considered safe. The most common adverse effects are hypersensitivity, injection site reactions, and other adverse effects specific to the injection site.¹²¹ Additionally, the cosmetic effects are transient, given the nature of the medication.

Trigger point injections

TPIs in the neck and shoulders are frequently used to treat tension headaches and various referred pain locations in the face and arms. Tension and depression frequently overlap in clinical practice.¹²² Relieving muscle tension (with resulting trigger points) improves muscle function and mood.

Continue to: The higher the number of active...

The higher the number of active trigger points (TPs), the greater the physical burden of headache and the higher the anxiety level. Gender differences in TP prevalence and TPI efficacy have been described in the literature. For example, the number of active TPs seems directly associated with anxiety levels in women but not in men.¹²³ Although TPs appear to be more closely associated with anxiety than depression,¹²⁴ depression associated with muscle tension does improve with TPIs. European studies have demonstrated a decrease in scores on the Hamilton Depression Rating Scale and Hamilton Anxiety Rating Scale following TPI treatment.¹²⁵ The effect may be indirect, as when a patient’s pain is relieved, sleep and other psychiatric symptoms improve.¹²⁶

A randomized controlled trial by Castro Sánchez et al¹²⁷ demonstrated that dry needling therapy in patients with fibromyalgia syndrome (FMS) showed improvements in pain pressure thresholds, body pain, vitality, and social function, as well as total FMS symptoms, quality of sleep, anxiety, hospital anxiety and depression, general pain intensity, and fatigue.

Myofascial pain syndrome, catastrophizing, and muscle tension are common in patients with depression, anxiety, and somatization. Local TPI therapy aimed at inactivating pain generators is supported by moderate quality evidence. All manner of therapies have been described, including injection of saline, corticosteroids, local anesthetic agents, and dry needling. BT injections in chronic TPs are also practiced, though no specific injection therapy has been reliably shown to be more advantageous than another. The benefits of TPIs may be derived from the needle itself rather than from any specific substance injected. Stimulation of a local twitch response with direct needling of the TP appears of importance. There is no established consensus regarding the number of injection points, frequency of administration, and volume or type of injectate.¹²⁸

Adverse effects of TPIs relate to the nature of the invasive therapy, with the risk of tissue damage and bleeding. Pneumothorax risk is present with needle insertion at the neck and thorax.¹²⁹ Patients with diabetes may experience variations in blood sugar control if steroids are used.

Bottom Line

Interventional treatment modalities that may have a role in psychiatric treatment include IV administration of ketamine, aducanumab, lecanemab, brexanolone, magnesium, scopolamine, and clomipramine. Other interventional approaches include stellate ganglion blocks, glabellar botulinum toxin injections, and trigger point injections.

Related Resources

• Dokucu ME, Janicak PG. Nontraditional therapies for treatment-resistant depression. Current Psychiatry. 2021; 20(9):38-43,49. doi:10.12788/cp.0166
• Kim J, Khoury R, Grossberg GT. Botulinum toxin: emerging psychiatric indications. Current Psychiatry. 2018;17(12):8-18.

Drug Brand Names

Aducanumab • Aduhelm
Aripiprazole • Abilify
Aripiprazole lauroxil • Aristada
Brexanolone • Zulresso
Buprenorphine • Sublocade
Citalopram • Celexa
Clomipramine • Anafranil
Diazepam • Valium
Droperidol • Inapsine
Esketamine • Spravato
Fentanyl • Actiq
Fluphenazine decanoate • Modecate
Fluphenazine hydrochloride • Prolixin
Haloperidol decanoate • Haldol decanoate
Haloperidol lactate • Haldol
Ketamine • Ketalar
Lecanemab • Leqembi
Lidocaine • Xylocaine
Lorazepam • Ativan
Loxapine inhaled • Adasuve
Naltrexone • Vivitrol
Magnesium sulfate • Sulfamag
Midazolam • Versed
Olanzapine • Zyprexa
OnabotulinumtoxinA injection • Botox
Paliperidone • Invega Hafyera, Invega Sustenna, Invega Trinza
Rapamycin • Rapamune, Sirolimus
Risperidone • Perseris
Risperidone microspheres • Risperdal Consta, Rykindo
Scopolamine • Hyoscine
Tramadol • Conzip
Vortioxetine • Trintellix
Ziprasidone • Geodon

Advances in the understanding of neurobiological and neuro­psychiatric pathophysiology have opened new avenues of treatment for psychiatric patients. Historically, with a few exceptions, most psychiatric medications have been administered orally. However, many of the newer treatments require some form of specialized administration because they cannot be taken orally due to their chemical property (such as aducanumab); because there is the need to produce stable blood levels of the medication (such as brexanolone); because oral administration greatly diminished efficacy (such as oral vs IV magnesium or scopolamine), or because the treatment is focused on specific brain structures. This need for specialized administration has created a subspecialty called interventional psychiatry.

Part 1 of this 2-part article provides an overview of 1 type of interventional psychiatry: parenterally administered medications, including those administered via IV. We also describe 3 other interventional approaches to treatment: stellate ganglion blocks, glabellar botulinum toxin (BT) injections, and trigger point injections. In Part 2 we will review interventional approaches that involve neuromodulation.

Parenteral medications in psychiatry

In general, IV and IM medications can be more potent that oral medications due to their overall faster onset of action and higher blood concentrations. These more invasive forms of administration can have significant limitations, such as a risk of infection at the injection site, the need to be administered in a medical setting, additional time, and patient discomfort.

Table 1 lists short-acting injectable medications used in psychiatry, and Table 2 lists long-acting injectable medications. Parenteral administration of antipsychotics is performed to alleviate acute agitation or for chronic symptom control. These medications generally are not considered interventional treatments, but could be classified as such due to their invasive nature.¹ Furthermore, inhalable loxapine—which is indicated for managing acute agitation—requires a Risk Evaluation and Mitigation Strategy program consisting of 2 hours observation and monitoring of respiratory status.^2,3 Other indications for parenteral treatments include IM naltrexone extended release⁴ and subcutaneous injections of buprenorphine extended release⁵ and risperidone.⁶

IV administration

Most IV treatments described in this article are not FDA-approved for psychiatric treatment. Despite this, many interventional psychiatric treatments are part of clinical practice. IV infusion of ketamine is the most widely known and most researched of these. Table 3 lists other IV treatments that could be used as psychiatric treatment.

Ketamine

Since the early 1960s, ketamine has been used as a surgical anesthetic for animals. In the United States, it was approved for human surgical anesthesia in 1970. It was widely used during the Vietnam War due to its lack of inhibition of respiratory drive; medical staff first noticed an improvement in depressive symptoms and the resolution of suicidal ideation in patients who received ketamine. This led to further research on ketamine, particularly to determine its application in treatment-resistant depression (TRD) and other conditions.⁷ IV ketamine administration is most widely researched, but IM injections, intranasal sprays, and lozenges are also available. The dissociative properties of ketamine have led to its recreational use.⁸

Hypotheses for the mechanism of action of ketamine as an antidepressant include direct synaptic or extrasynaptic (GluN2B-selective), N-methyl-D-aspartate receptor (NMDAR) inhibition, selectively greater inhibition of NMDARs localized on GABAergic (gamma-aminobutyric acid) interneurons, and the role of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor activation. There are links between ketamine’s antidepressant actions and downstream mechanisms regulating synaptic plasticity, including brain-derived neurotrophic factor, eukaryotic elongation factor 2, mammalian target of rapamycin, and glycogen synthase kinase-3. Multiple other ketamine-associated mechanisms also have been described.^9,10 Action on the mu-opioid receptor is also known, possibly contributing to both antidepressant and anesthetic properties of ketamine.¹¹ Rapid onset of ketamine antidepressant action is especially valuable.¹²

Continue to: Ketamine is a schedule...

Ketamine is a schedule III medication with addictive properties. Delirium, panic attacks, hallucinations, nightmares, dysphoria, and paranoia may occur during and after use.¹³ Premedication with benzodiazepines, most notably lorazepam, is occasionally used to minimize ketamine’s adverse effects, but this generally is not recommended because doing so reduces ketamine’s antidepressant effects.¹⁴ Driving and operating heavy machinery is contraindicated after IV infusion. The usual protocol involves an IV infusion of ketamine 0.4 mg/kg to 1 mg/kg dosing over 1 hour. Doses between 0.4 mg/kg and 0.6 mg/kg are most common. Ketamine has a therapeutic window; doses >0.5 mg/kg are progressively less effective.¹⁵ Unlike the recommendation after esketamine administration, after receiving ketamine, patients remain in the care of their treatment team for <2 hours.

Esketamine, the S enantiomer of ketamine, was FDA-approved for TRD as an intranasal formulation. Esketamine is more commonly used than IV ketamine because it is FDA-approved and typically covered by insurance, but it may not be as effective.¹⁶ An economic analysis by Brendle et al¹⁷ suggested insurance companies would lower costs if they covered ketamine infusions vs intranasal esketamine.

Aducanumab and lecanemab

The most recent FDA-approved interventional agents are aducanumab and lecanemab, which are indicated for treating Alzheimer disease.^18,19 Both are human monoclonal antibodies that bind selectively and with high affinity to amyloid beta plaque aggregates and promote their removal by Fc receptor–mediated phagocytosis.²⁰

FDA approval of aducanumab and lecanemab was controversial. Initially, aducanumab’s safety monitoring board performed a futility analysis that suggested aducanumab was unlikely to separate from placebo, and the research was stopped.²¹ The manufacturer petitioned the FDA to consider the medication for accelerated approval on the basis of biomarker data showing that amyloid beta plaque aggregates become smaller. Current FDA approval is temporary to allow patients access to this potentially beneficial agent, but the manufacturer must supply clinical evidence that the reduction of amyloid beta plaques is associated with desirable changes in the course of Alzheimer disease, or risk losing the approval.

Lecanemab is also a human monoclonal antibody intended to remove amyloid beta plaques that was FDA-approved under the accelerated approval pathway.²² Unlike aducanumab, lecanemab demonstrated a statistically significant (although clinically imperceptible) reduction in the rate of cognitive decline; it did not show cognitive improvement.²³ Lecanemab also significantly reduced amyloid beta plaques.²³

Continue to: Aducanumab and lecanemab are generally...

Aducanumab and lecanemab are generally not covered by insurance and typically cost >$26,000 annually. Both are administered by IV infusion once a month. More monoclonal antibody medications for treating early Alzheimer disease are in the late stages of development, most notably donanebab.²⁴ Observations during clinical trials found that in the later stages of Alzheimer disease, forceful removal of plaques by the autoimmune process damages neurons, while in less dense deposits of early dementia such removal is not harmful to the cells and prevents amyloid buildup.

Brexanolone

Brexanolone is an aqueous formulation of allopregnanolone, a major metabolite of progesterone and a positive allosteric modulator of GABA-A receptors.²⁵ Its levels are maximal at the end of the third trimester of pregnancy and fall rapidly following delivery. Research showed a 3-day infusion was rapidly and significantly effective for treating postpartum depression²⁶ and brexanolone received FDA approval for this indication in March 2019.²⁷ However, various administrative, economic, insurance, and other hurdles make it difficult for patients to access this treatment. Despite its rapid onset of action (usually 48 hours), brexanolone takes an average of 15 days to go through the prior authorization process.²⁸ In addition to the need for prior authorization, the main impediment to the use of brexanolone is the 3-day infusion schedule, which greatly magnifies the cost but is partially circumvented by the availability of dedicated outpatient centers.

Magnesium

Magnesium is on the World Health Organization’s Model List of Essential Medicines.²⁹ There has been extensive research on the use of magnesium sulfate for psychiatric indications, especially for depression.³⁰ Magnesium functions similarly to calcium channel blockers by competitively blocking intracellular calcium channels, decreasing calcium availability, and inhibiting smooth muscle contractility.³¹ It also competes with calcium at the motor end plate, reducing excitation by inhibiting the release of acetylcholine.³² This property is used for high-dose IV magnesium treatment of impending preterm labor in obstetrics. Magnesium sulfate is the drug of choice in treating eclamptic seizures and preventing seizures in severe preeclampsia or gestational hypertension with severe features.³³ It is also used to treat torsade de pointes, severe asthma exacerbations, constipation, and barium poisoning.³⁴ Beneficial use in asthma treatment³⁵ and the treatment of migraine³⁶ have also been reported.

IV magnesium in myocardial infarction may be harmful,³⁷ though outside of acute cardiac events, magnesium is found to be safe.³⁸

Oral magnesium sulfate is a common over-the-counter anxiety remedy. As a general cell stabilizer (mediated by the reduction of intracellular calcium), magnesium is potentially beneficial outside of its muscle-relaxing properties, although muscle relaxing can benefit anxious patients. It is used to treat anxiety,³⁹ alcohol withdrawal,⁴⁰ and fear.⁴¹ Low magnesium blood levels are found in patients with depression, schizophrenia,⁴² and attention-deficit/hyperactivity disorder.⁴³ However, it is important to note that the therapeutic effect of magnesium when treating anxiety and headache is independent of preinfusion magnesium blood levels.⁴³

Continue to: The efficacy of oral magnesium...

The efficacy of oral magnesium is not robust. However, IV administration has a pronounced beneficial effect as an abortive and preventative treatment in many patients with anxiety.⁴⁴

IV administration of magnesium can produce adverse effects, including flushing, sweating, hypotension, depressed reflexes, flaccid paralysis, hypothermia, circulatory collapse, and cardiac and CNS depression. These complications are very rare and dose-dependent.⁴⁵ Magnesium is excreted by the kidneys, and dosing must be decreased in patients with kidney failure. The most common adverse effect is local burning along the vein upon infusion; small doses of IV lidocaine can remedy this. Hot flashes are also common.⁴⁵

Various dosing strategies are available. In patients with anxiety, application dosing is based on the recommended preeclampsia IV dose of 4 g diluted in 250 mL of 5% dextrose. Much higher doses may be used in obstetrics. Unlike in obstetrics, for psychiatric indications, magnesium is administered over 60 to 90 minutes. Heart monitoring is recommended.

Scopolamine

Scopolamine is primarily used to relieve nausea, vomiting, and dizziness associated with motion sickness and recovery from anesthesia. It is also used in ophthalmology and in patients with excessive sweating. In off-label and experimental applications, scopolamine has been used in patients with TRD.⁴⁶

Scopolamine is an anticholinergic medication. It is a nonselective antagonist at muscarinic receptors.⁴⁷ Tricyclic antidepressants (TCAs) possess strong anticholinergic function. Newer generations of antidepressants were designed specifically not to have this function because it was believed to be an unwanted and potentially dangerous adverse effect. However, data suggest that anticholinergic action is important in decreasing depressive symptoms. Several hypotheses of anticholinergic effects on depression have been published since the 1970s. They include the cholinergic-adrenergic hypothesis,⁴⁸ acetylcholine predominance relative to adrenergic action hypothesis,⁴⁹ and insecticide poisoning observations.⁵⁰ Centrally acting physostigmine (but not peripherally acting neostigmine) was reported to control mania.^48,51 A genetic connection between the M2acetylcholine receptor in patients with major depressive disorder (MDD) and alcohol use disorder is also suggestive.⁵²

Continue to: Multiple animal studies show...

Multiple animal studies show direct improvement in mobility and a decrease in despair upon introducing anticholinergic substances.^53-55 The cholinergic theory of depression has been studied in several controlled clinical human studies.^56,57 Use of a short-acting anticholinergic glycopyrrolate during electroconvulsive therapy (ECT) may contribute to the procedure’s efficacy.

Human research shows scopolamine has a higher efficacy as an antidepressant and anti-anxiety medication in women than in men,⁵⁸ possibly because estrogen increases the activity of choline acetyltransferase and release of acetylcholine.^59,60 M2receptors mediate estrogen influence on the NMDAR, which may explain the anticholinergic effects of depression treatments in women.⁶¹

Another proposed mechanism of action of scopolamine is a potent inhibition of the NMDAR.⁶² Rapid treatments of depression may be based on this mechanism. Examples of such treatments include IV ketamine and sleep deprivation.⁶³ IV scopolamine shows potency in treating MDD and bipolar depression. This treatment should be reserved for patients who do not respond to or are not candidates for other usual treatment modalities of MDD and for the most severe cases. Scopolamine is 30 times more potent than amitriptyline in anticholinergic effect and reportedly produces sustained improvement in MDD.⁶⁴

Scopolamine has no black-box warnings. It has not been studied in pregnant women and is not recommended for use during pregnancy. Due to possible negative cardiovascular effects, a normal electrocardiogram is required before the start of treatment. Exercise caution in patients with glaucoma, benign prostatic enlargement, gastroparesis, unstable cardiovascular status, or severe renal impairment.

Treatment with scopolamine is not indicated for patients with myasthenia gravis, psychosis, or seizures. Patients must be off potassium for 3 days before beginning scopolamine treatment. Patients should consult with their cardiologist before having a scopolamine infusion. Adverse reactions may include psychosis, tachycardia, seizures, paralytic ileus, and glaucoma exacerbation. The most common adverse effects of scopolamine infusion treatment include drowsiness, dry mouth, blurred vision, lightheadedness, and dizziness. Due to possible drowsiness, operating motor vehicles or heavy machinery must be avoided on the day of treatment.⁶⁵ Overall, the adverse effects of scopolamine are preventable and manageable, and its antidepressant efficacy is noteworthy.⁶⁶

Continue to: Treatment typically consists of 3 consecutive infusions...

Treatment typically consists of 3 consecutive infusions of 4 mcg/kg separated by 3 to 5 days.⁵⁶ It is possible to have a longer treatment course if the patient experiences only partial improvement. Repeated courses or maintenance treatment (similar to ECT maintenance) are utilized in some patients if indicated. Cardiac monitoring is mandatory.

Clomipramine

Clomipramine, a TCA, acts as a preferential inhibitor of 5-hydroxytryptamine uptake and has proven effective in managing depression, TRD, and obsessive-compulsive disorder (OCD).⁶⁷ Although this medication has reported treatment benefits for patients with phobia, panic disorder,¹⁵ chronic pain,⁶⁸ Tourette syndrome,⁶⁹ premature ejaculation, anorexia nervosa,⁷⁰ cataplexy,⁴⁹ and enuresis,⁷¹ it is FDA-approved only for the treatment of OCD.⁷² Clomipramine may also be beneficial for pain and headache, possibly because of its anti-inflammatory action.⁷³ The anticholinergic effects of clomipramine may add to its efficacy in depression.

The pathophysiology of MDD is connected to hyperactivity of the HPA axis and elevated cortisol levels. Higher clomipramine plasma levels show a linear correlation with lower cortisol secretion and levels, possibly aiding in the treatment of MDD and anxiety.⁷⁴ The higher the blood level, the more pronounced clomipramine’s therapeutic effect across multiple domains.⁷⁵

IV infusion of clomipramine produces the highest concentration in the shortest time, but overall, research does not necessarily support increased efficacy of IV over oral administration. There is evidence suggesting that subgroups of patients with severe, treatment-refractory OCD may benefit from IV agents and research suggests a faster onset of action.⁷⁶ Faster onset of symptom relief is the basis for IV clomipramine use. In patients with OCD, it can take several months for oral medications to produce therapeutic benefits; not all patients can tolerate this. In such scenarios, IV administration may be considered, though it is not appropriate for routine use until more research is available. Patients with treatment-resistant OCD who have exhausted other means of symptom relief may also be candidates for IV treatment.

The adverse effects of IV clomipramine are no different from oral use, though they may be more pronounced. A pretreatment cardiac exam is desirable because clomipramine, like other TCAs, may be cardiotoxic. The anticholinergic adverse effects of TCAs are well known to clinicians⁷⁷ and partially explained in the scopolamine section of this article. It is not advisable to combine clomipramine with other TCAs or serotonin reuptake inhibitors. Clomipramine also should not be combined with monoamine oxidase inhibitors, though such a combination was reported in medical literature.⁷⁸ Combination with antiarrhythmics such as lidocaine or opioids such as fentanyl or and tramadol is highly discouraged (fentanyl and tramadol also have serotonergic effects).⁷⁹

Continue to: Clomipramine for IV use is not commercially available...

Clomipramine for IV use is not commercially available and must be sterilely compounded. The usual course of treatment is a series of 3 infusions: 150 mg on Day 1, 200 mg on Day 2 or Day 3, and 250 mg on Day 3, Day 4, or Day 5, depending on tolerability. A protocol with a 50 mg/d starting dose and titration up to a maximum dose of 225 mg/d over 5 to 7 days has been suggested for inpatient settings.⁶⁷ Titration to 250 mg is more common.⁸⁰

A longer series may be performed, but this increases the likelihood of adverse effects. Booster and maintenance treatments are also completed when required. Cardiac monitoring is mandatory.

Vortioxetine and citalopram

IV treatment of depression with vortioxetine and citalopram has been explored but has not yet taken hold in clinical psychiatry.^81,82

Injections and blocks

Three interventional approaches to treatment that possess psychotherapeutic potential include stellate ganglion blocks (SGBs), glabellar BT injections, and trigger point injections (TPIs). None of these are FDA-approved for psychiatric treatment.

Stellate ganglion blocks

The sympathetic nervous system is involved in autonomic hyperarousal and is at the core of posttraumatic symptomatology.⁸³ Insomnia, anxiety, irritability, hypervigilance, and other excitatory CNS events are connected to the sympathetic nervous system and amygdala activation is commonly observed in those exposed to extreme stress or traumatic events.⁸⁴

Continue to: SGBs were first performed 100 years ago...

SGBs were first performed 100 years ago and reported to have beneficial psychiatric effects at the end of the 1940s. In 1998 in Finland, improvement of posttraumatic stress disorder (PTSD) symptoms was observed accidentally via thoracic level spine blocks.⁸⁵ In 2006, cervical level sympathetic blocks were shown to be effective for PTSD symptom control.⁸⁶ By the end of 2010, Veterans Administration hospitals adopted SGBs to treat veterans with PTSD.^87,88 The first multisite, randomized clinical trial of SGB for PTSD confirmed multiple previous reports of treatment efficacy. Specifically, 2 SGB treatments 2 weeks apart effectively reduced total symptom severity scores over 8 weeks.⁸⁷

Since the stellate ganglion is connected to the amygdala, SGB has also been assessed for treating anxiety and depression.^89,90 Outside of PTSD, SGBs are used to treat complex regional pain syndrome,⁹¹ phantom limb pain, trigeminal neuralgia,⁹² intractable angina,⁹³ and postherpetic neuralgia in the head, neck, upper chest, or arms.⁹⁴ The procedure consists of an injection of a local anesthetic through a 25-gauge needle into the stellate sympathetic ganglion at the C6 or C7 vertebral levels. An injection into C6 is considered safer because of specific cervical spine anatomy. Ideally, fluoroscopic guidance or ultrasound is used to guide needle insertion.⁹⁵

A severe drop in blood pressure may be associated with SGBs and is mitigated by IV hydration. Other adverse effects include red eyes, drooping of the eyelids, nasal congestion, hoarseness, difficulty swallowing, a sensation of a “lump” in the throat, and a sensation of warmth or tingling in the arm or hand. Bilateral SGB is contraindicated due to the danger of respiratory arrest.⁹⁶

Glabellar BT injections

OnabotulinumtoxinA (BT) injection was first approved for therapeutic use in 1989 for eye muscle disorders such as strabismus⁹⁷ and blepharospasm.⁹⁸ It was later approved for several other indications, including cosmetic use, hyperhidrosis, migraine prevention, neurogenic bladder disorder, overactive bladder, urinary incontinence, and spasticity.^99-104 BT is used off-label for achalasia and sialorrhea.^105,106 Its mechanism of action is primarily attributed to muscle paralysis by blocking presynaptic acetylcholine release into neuromuscular junctions.¹⁰⁷

Facial BT injections are usually administered for cosmetic purposes, but smoothing forehead wrinkles and frown lines (the glabellar region of the face) both have antidepressant effects.¹⁰⁸ BT injections into the glabellar region also demonstrate antidepressant effects, particularly in patients with comorbid migraines and MDD.¹⁰⁹ Early case observations supported the independent benefit of the toxin on MDD when the toxin was injected into the glabellar region.^110,111 The most frequent protocol involves injections in the procerus and corrugator muscles.

Continue to: The facial feedback/emotional proprioception hypothesis...

The facial feedback/emotional proprioception hypothesis has dominated thinking about the mood-improving effects of BT. The theory is that blocking muscular expression of sadness (especially in the face) interrupts the experience of sadness; therefore, depression subsides.^112,113 However, BT injections in the muscles involved in the smile and an expression of positive emotions (lateral part of the musculus orbicularis oculi) have been associated with increased MDD scores.¹¹⁴ Thus, the mechanism clearly involves more than the cosmetic effect, since facial muscle injections in rats also have antidepressant effects.¹¹⁵

The use of progressive muscle relaxation is well-established in psychiatric treatment. The investigated conditions of increased muscle tone, especially torticollis and blepharospasm, are associated with MDD, and it may be speculated that proprioceptive feedback from the affected muscles may be causally involved in this association.^116-118 Activity of the corrugator muscle has been positively associated with increased amygdala activity.¹¹⁹ This suggests a potential similar mechanism to that hypothesized for SGB.

Alternatively, BT is commonly used to treat chronic conditions that may contribute to depression; its success in relieving the underlying problem may indirectly relieve MDD. Thus, in a postmarketing safety evaluation of BT, MDD was demonstrated 40% to 88% less often by patients treated with BT for 6 of the 8 conditions and injection sites, such as in spasms and spasticity of arms and legs, torticollis and neck pain, and axilla and palm injections for hyperhidrosis. In a parotid and submandibular glands BT injection subcohort, no patients experienced depressive symptoms.¹²⁰

Medicinal BT is generally considered safe. The most common adverse effects are hypersensitivity, injection site reactions, and other adverse effects specific to the injection site.¹²¹ Additionally, the cosmetic effects are transient, given the nature of the medication.

Trigger point injections

TPIs in the neck and shoulders are frequently used to treat tension headaches and various referred pain locations in the face and arms. Tension and depression frequently overlap in clinical practice.¹²² Relieving muscle tension (with resulting trigger points) improves muscle function and mood.

Continue to: The higher the number of active...

The higher the number of active trigger points (TPs), the greater the physical burden of headache and the higher the anxiety level. Gender differences in TP prevalence and TPI efficacy have been described in the literature. For example, the number of active TPs seems directly associated with anxiety levels in women but not in men.¹²³ Although TPs appear to be more closely associated with anxiety than depression,¹²⁴ depression associated with muscle tension does improve with TPIs. European studies have demonstrated a decrease in scores on the Hamilton Depression Rating Scale and Hamilton Anxiety Rating Scale following TPI treatment.¹²⁵ The effect may be indirect, as when a patient’s pain is relieved, sleep and other psychiatric symptoms improve.¹²⁶

A randomized controlled trial by Castro Sánchez et al¹²⁷ demonstrated that dry needling therapy in patients with fibromyalgia syndrome (FMS) showed improvements in pain pressure thresholds, body pain, vitality, and social function, as well as total FMS symptoms, quality of sleep, anxiety, hospital anxiety and depression, general pain intensity, and fatigue.

Myofascial pain syndrome, catastrophizing, and muscle tension are common in patients with depression, anxiety, and somatization. Local TPI therapy aimed at inactivating pain generators is supported by moderate quality evidence. All manner of therapies have been described, including injection of saline, corticosteroids, local anesthetic agents, and dry needling. BT injections in chronic TPs are also practiced, though no specific injection therapy has been reliably shown to be more advantageous than another. The benefits of TPIs may be derived from the needle itself rather than from any specific substance injected. Stimulation of a local twitch response with direct needling of the TP appears of importance. There is no established consensus regarding the number of injection points, frequency of administration, and volume or type of injectate.¹²⁸

Adverse effects of TPIs relate to the nature of the invasive therapy, with the risk of tissue damage and bleeding. Pneumothorax risk is present with needle insertion at the neck and thorax.¹²⁹ Patients with diabetes may experience variations in blood sugar control if steroids are used.

Bottom Line

Interventional treatment modalities that may have a role in psychiatric treatment include IV administration of ketamine, aducanumab, lecanemab, brexanolone, magnesium, scopolamine, and clomipramine. Other interventional approaches include stellate ganglion blocks, glabellar botulinum toxin injections, and trigger point injections.

Related Resources

• Dokucu ME, Janicak PG. Nontraditional therapies for treatment-resistant depression. Current Psychiatry. 2021; 20(9):38-43,49. doi:10.12788/cp.0166
• Kim J, Khoury R, Grossberg GT. Botulinum toxin: emerging psychiatric indications. Current Psychiatry. 2018;17(12):8-18.

Drug Brand Names

Aducanumab • Aduhelm
Aripiprazole • Abilify
Aripiprazole lauroxil • Aristada
Brexanolone • Zulresso
Buprenorphine • Sublocade
Citalopram • Celexa
Clomipramine • Anafranil
Diazepam • Valium
Droperidol • Inapsine
Esketamine • Spravato
Fentanyl • Actiq
Fluphenazine decanoate • Modecate
Fluphenazine hydrochloride • Prolixin
Haloperidol decanoate • Haldol decanoate
Haloperidol lactate • Haldol
Ketamine • Ketalar
Lecanemab • Leqembi
Lidocaine • Xylocaine
Lorazepam • Ativan
Loxapine inhaled • Adasuve
Naltrexone • Vivitrol
Magnesium sulfate • Sulfamag
Midazolam • Versed
Olanzapine • Zyprexa
OnabotulinumtoxinA injection • Botox
Paliperidone • Invega Hafyera, Invega Sustenna, Invega Trinza
Rapamycin • Rapamune, Sirolimus
Risperidone • Perseris
Risperidone microspheres • Risperdal Consta, Rykindo
Scopolamine • Hyoscine
Tramadol • Conzip
Vortioxetine • Trintellix
Ziprasidone • Geodon

CASE Depressed and anxious

Five years ago, Ms. X, age 60, was diagnosed with treatment-resistant major depressive disorder (MDD) with anxiety. This diagnosis was established by a previous psychiatrist. She presents to a clinic for a second opinion.

Since her diagnosis, Ms. X has experienced sad mood, anhedonia, difficulty falling asleep, increased appetite and weight, and decreased concentration and attention. Her anxiety stems from her inability to work, which causes her to worry about her children. In the clinic, the treatment team conducts the Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder-7 item scale (GAD-7) with Ms. X. She scores 16 on the PHQ-9, indicating moderately severe depression, and scores 12 on the GAD-7, indicating moderate anxiety.

Ms. X’s current medication regimen consists of venlafaxine extended-release (XR) 225 mg/d, trazodone 100 mg/d at bedtime, and clonazepam 1 mg twice daily. She reports no significant improvement of her symptoms from these medications. Additionally, Ms. X reports that in the past she had been prescribed fluoxetine, citalopram, and duloxetine, but she cannot recall the dosages.

Ms. X appears appropriately groomed, maintains appropriate eye contact, has clear speech, and does not show evidence of internal stimulation; however, she has difficulty following instructions. She makes negative comments about herself such as “I’m worthless” and “Nobody cares about me.” The treatment team decides to taper Ms. X off venlafaxine XR and initiates sertraline 50 mg/d, while continuing trazodone 50 mg/d at bedtime and clonazepam 1 mg twice daily. The team refers her for cognitive-behavioral therapy (CBT) to address her cognitive distortions, sad mood, and anxiety. Ms. X is asked to follow up with Psychiatry in 1 week.

EVALUATION Unusual behavior

At her CBT intake, Ms. X endorses depression and anxiety. Her PHQ-9 score at this visit is 19 (moderately severe depression) and GAD-7 score is 16 (severe anxiety). The psychologist notes that Ms. X is able to complete activities of daily living and instrumental activities of daily living without assistance. Ms. X denies any use of illicit substances or alcohol. No gross memory impairment is noted during this appointment, though Ms. X exhibits unusual behavior, including exiting and re-entering the clinic multiple times to repeatedly ask about follow-up appointments. The psychologist concludes that Ms. X’s presentation and behavior can be explained by MDD and pseudodementia.

[polldaddy:12189562]

The authors’ observations

Pseudodementia gained recognition in clinical research >100 years ago.¹ Officially coined by Kiloh in 1961, the term was used broadly to categorize psychiatric cases that present like dementia but are the result of reversible causes. More recently, it has been used to describe older adults who present with cognitive deficits in the context of depressive symptoms.² The goal of evaluation is to determine if the primary issue is a cognitive disorder or a depressive episode. DSM-5-TR does not classify pseudodementia as a distinct diagnosis, but instead categorizes its symptoms as components under other major diagnostic categories. Patients can present with MDD and associated cognitive symptoms, or with a cognitive disorder with depressive symptoms, which would be diagnosed as a cognitive disorder with a major depressive-like episode.³

Pseudodementia is rare. Brodaty et al⁴ found the prevalence of pseudodementia in primary care settings was 0.6%. Older adults (age >65) who live alone are at increased risk of developing pseudodementia, which can be worsened by poor social support and acute psychosocial and environmental changes.⁵ A key characteristic of this disorder is that as the patient’s depressed mood improves, their memory and cognition also improve.⁶Table 1^3,6 outlines overlapping features of MDD and pseudodementia.

Continue to: EVALUATION Worsening depression

At her Psychiatry follow-up appointment, Ms. X reports that her mood is worse since she ended the relationship with her partner and she feels anxious because the partner was financially supporting her. Her PHQ-9 score is 24 (severe depression) and her GAD-7 score is 12 (moderate anxiety). Ms. X reports tolerating her transition from venlafaxine XR 225 mg/d to sertraline 50 mg/d well.

Additionally, Ms. X reports her children have called her “useless” since she continues to have difficulties following through on household tasks, even though she has no physical impairments that prevent her from completing them. The Psychiatry team observes that Ms. X has no problems walking or moving her arms or legs.

The Psychiatry team administers the Montreal Cognitive Assessment (MoCA). Ms. X scores 22, indicating mild impairment.

The team recommends a neuropsychological assessment to determine if this MoCA score is due to a cognitive disorder or is rooted in her mood symptoms. The team also recommends an MRI of the brain, complete blood count (CBC), comprehensive metabolic panel (CMP), and urinalysis (UA).

[polldaddy:12189567]

Continue to: The authors' observations

Neuropsychological assessments are important tools for exploring the behavioral manifestations of brain dysfunction (Table 2).⁷ These assessments factor in elements of neurology, psychiatry, and psychology to provide information about the diagnosis, prognosis, and functional status of patients with medical conditions, especially those with neurocognitive and psychiatric disorders. They combine information from the patient and collateral interviews, behavioral observations, a review of patient records, and objective tests of motor, emotional, and cognitive function.

Among other uses, neuropsychological assessments can help identify depression in patients with neurologic impairment, determine the diagnosis and plan of care for patients with concussions, determine the risk of a motor vehicle crash in patients with cognitive impairment, and distinguish Alzheimer disease from vascular dementia.⁸ Components of such assessments include the Beck Anxiety Inventory (BAI) to assess anxiety, the Dementia Rating Scale-2 and Neuropsychological Assessment Battery-Screening Module to assess dementia, and the Beck Depression Inventory (BDI) to assess depression.⁹

EVALUATION Continued cognitive decline

A different psychologist performs the neuro­psychological assessment, who conducts the Repeatable Battery for the Assessment of Neuropsychological Status Update to determine if Ms. X is experiencing cognitive impairment. Her immediate memory, visuospatial/constructions, language, attention, and delayed memory are significantly impaired for someone her age. The psychologist also administers the Wechsler Adult Intelligence Scale IV and finds Ms. X’s general cognitive ability is within the low average range of intellectual functioning as measured by Full-Scale IQ. Ms. X scores 29 on the BDI-II, indicating significant depressive symptoms, and 13 on the BAI, indicating mild anxiety symptoms.

Ms. X is diagnosed with MDD and an unspecified neurocognitive disorder. The psychologist recommends she start CBT to address her mood and anxiety symptoms.

Upon reviewing the results with Ms. X, the treatment team again recommends a brain MRI, CBC, CMP, and UA to rule out organic causes of her cognitive decline. Ms. X decides against the MRI and laboratory workup and elects to continue her present medication regimen and CBT.

Several weeks later, Ms. X’s family brings her to the emergency department (ED) for evaluation of worsening mood, decreased personal hygiene, increased irritability, and further cognitive decline. They report she is having an increasingly difficult time remembering things such as where she parked her car. The ED team decides to discontinue clonazepam but continues sertraline and trazodone.

Continue to: CBC, CMP, and UA...

CBC, CMP, and UA are unremarkable. Ms. X undergoes a brain CT scan without contrast, which reveals hyperdense lesions in the inferior left tentorium, posterior fossa. A subsequent brain MRI with contrast reveals a dural-based enhancing mass, inferior to the left tentorium, in the left posterior fossa measuring 2.2 cm x 2.1 cm, suggestive of a meningioma. The team orders a Neurosurgery consult.

[polldaddy:12189571]

The authors’ observations

While most brain tumors are secondary to metastasis, meningiomas are the most common primary CNS tumor. Typically, they are asymptomatic; their diagnosis is often delayed until the patient presents with psychiatric symptoms without any focal neurologic findings. The frontal lobe is the most common location of meningioma. Data from 48 case reports of patients with meningiomas and psychiatric symptoms suggest symptoms do not always correlate with specific brain regions.^10,11

Indications for neuroimaging in cases such as Ms. X include an abrupt change in behavior or personality, lack of response to psychiatric treatment, presence of focal neurologic signs, and an unusual psychiatric presentation and development of symptoms.¹¹

TREATMENT Neurosurgery

Neurosurgery recommends and performs a suboccipital craniotomy for biopsy and resection. Ms. X tolerates the procedure well. A meningioma is found in the posterior fossa, near the cerebellar convexity. A biopsy finds no evidence of malignancies.

At her postoperative follow-up appointment several days after the procedure, Ms. X reports new-onset hearing loss and tinnitus.

[polldaddy:12189747]

Continue to: The authors' observations

Patients who require neurosurgery typically already carry a heavy psychiatric burden, which makes it challenging to determine the exact psychiatric consequences of neuro­surgery.^12-14 For example, research shows that temporal lobe resection and temporal lobectomy for treatment-resistant epilepsy can lead to an exacerbation of baseline psychiatric symptoms and the development of new symptoms (31% to 34%).^15,16 However, Bommakanti et al¹³ found no new psychiatric symptoms after resection of meningiomas, and surgery seemed to play a role in ameliorating psychiatric symptoms in patients with intracranial tumors. Research attempting to document the psychiatric sequelae of neurosurgery has had mixed results, and it is difficult to determine what effects brain surgery has on mental health.

OUTCOME Minimal improvement

Several weeks after neurosurgery, Ms. X and her family report her mood is improved. Her PHQ-9 score improves to 15, but her GAD-7 score increases to 13, 1 point above her previous score.

The treatment team recommends Ms. X continue taking sertraline 50 mg/d and trazodone 50 mg/d at bedtime. Ms. X’s family reports her cognition and memory have not improved; her MoCA score increases by 1 point to 23. The treatment team discusses with Ms. X and her family the possibility that her cognitive problems maybe better explained as a neurocognitive disorder rather than as a result of the meningioma, since her MoCA score has not significantly improved. Ms. X and her family decide to seek a second opinion from a neurologist.

Bottom Line

Pseudodementia is a term used to describe older adults who present with cognitive issues in the context of depressive symptoms. Even in the absence of focal findings, neuroimaging should be considered as part of the workup in patients who continue to experience a progressive decline in mood and cognitive function.

Related Resources

• Moller MD, Parmenter BA, Lane DW. Neuropsychological testing: a useful but underutilized resource. Current Psychiatry. 2019;18(11):40-46,51.
• Pollak J. Psychological/neuropsychological testing: when to refer for reexamination. Current Psychiatry. 2021;20(9):18- 19,30-31,37. doi:10.12788/cp.0157

Drug Brand Names

Citalopram • Celexa
Clonazepam • Klonopin
Duloxetine • Cymbalta
Fluoxetine • Prozac
Sertraline • Zoloft
Trazodone • Oleptro
Venlafaxine extended- release • Effexor XR

CASE Depressed and anxious

Five years ago, Ms. X, age 60, was diagnosed with treatment-resistant major depressive disorder (MDD) with anxiety. This diagnosis was established by a previous psychiatrist. She presents to a clinic for a second opinion.

Since her diagnosis, Ms. X has experienced sad mood, anhedonia, difficulty falling asleep, increased appetite and weight, and decreased concentration and attention. Her anxiety stems from her inability to work, which causes her to worry about her children. In the clinic, the treatment team conducts the Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder-7 item scale (GAD-7) with Ms. X. She scores 16 on the PHQ-9, indicating moderately severe depression, and scores 12 on the GAD-7, indicating moderate anxiety.

Ms. X’s current medication regimen consists of venlafaxine extended-release (XR) 225 mg/d, trazodone 100 mg/d at bedtime, and clonazepam 1 mg twice daily. She reports no significant improvement of her symptoms from these medications. Additionally, Ms. X reports that in the past she had been prescribed fluoxetine, citalopram, and duloxetine, but she cannot recall the dosages.

Ms. X appears appropriately groomed, maintains appropriate eye contact, has clear speech, and does not show evidence of internal stimulation; however, she has difficulty following instructions. She makes negative comments about herself such as “I’m worthless” and “Nobody cares about me.” The treatment team decides to taper Ms. X off venlafaxine XR and initiates sertraline 50 mg/d, while continuing trazodone 50 mg/d at bedtime and clonazepam 1 mg twice daily. The team refers her for cognitive-behavioral therapy (CBT) to address her cognitive distortions, sad mood, and anxiety. Ms. X is asked to follow up with Psychiatry in 1 week.

EVALUATION Unusual behavior

At her CBT intake, Ms. X endorses depression and anxiety. Her PHQ-9 score at this visit is 19 (moderately severe depression) and GAD-7 score is 16 (severe anxiety). The psychologist notes that Ms. X is able to complete activities of daily living and instrumental activities of daily living without assistance. Ms. X denies any use of illicit substances or alcohol. No gross memory impairment is noted during this appointment, though Ms. X exhibits unusual behavior, including exiting and re-entering the clinic multiple times to repeatedly ask about follow-up appointments. The psychologist concludes that Ms. X’s presentation and behavior can be explained by MDD and pseudodementia.

[polldaddy:12189562]

The authors’ observations

Pseudodementia gained recognition in clinical research >100 years ago.¹ Officially coined by Kiloh in 1961, the term was used broadly to categorize psychiatric cases that present like dementia but are the result of reversible causes. More recently, it has been used to describe older adults who present with cognitive deficits in the context of depressive symptoms.² The goal of evaluation is to determine if the primary issue is a cognitive disorder or a depressive episode. DSM-5-TR does not classify pseudodementia as a distinct diagnosis, but instead categorizes its symptoms as components under other major diagnostic categories. Patients can present with MDD and associated cognitive symptoms, or with a cognitive disorder with depressive symptoms, which would be diagnosed as a cognitive disorder with a major depressive-like episode.³

Pseudodementia is rare. Brodaty et al⁴ found the prevalence of pseudodementia in primary care settings was 0.6%. Older adults (age >65) who live alone are at increased risk of developing pseudodementia, which can be worsened by poor social support and acute psychosocial and environmental changes.⁵ A key characteristic of this disorder is that as the patient’s depressed mood improves, their memory and cognition also improve.⁶Table 1^3,6 outlines overlapping features of MDD and pseudodementia.

Continue to: EVALUATION Worsening depression

At her Psychiatry follow-up appointment, Ms. X reports that her mood is worse since she ended the relationship with her partner and she feels anxious because the partner was financially supporting her. Her PHQ-9 score is 24 (severe depression) and her GAD-7 score is 12 (moderate anxiety). Ms. X reports tolerating her transition from venlafaxine XR 225 mg/d to sertraline 50 mg/d well.

Additionally, Ms. X reports her children have called her “useless” since she continues to have difficulties following through on household tasks, even though she has no physical impairments that prevent her from completing them. The Psychiatry team observes that Ms. X has no problems walking or moving her arms or legs.

The Psychiatry team administers the Montreal Cognitive Assessment (MoCA). Ms. X scores 22, indicating mild impairment.

The team recommends a neuropsychological assessment to determine if this MoCA score is due to a cognitive disorder or is rooted in her mood symptoms. The team also recommends an MRI of the brain, complete blood count (CBC), comprehensive metabolic panel (CMP), and urinalysis (UA).

[polldaddy:12189567]

Continue to: The authors' observations

Neuropsychological assessments are important tools for exploring the behavioral manifestations of brain dysfunction (Table 2).⁷ These assessments factor in elements of neurology, psychiatry, and psychology to provide information about the diagnosis, prognosis, and functional status of patients with medical conditions, especially those with neurocognitive and psychiatric disorders. They combine information from the patient and collateral interviews, behavioral observations, a review of patient records, and objective tests of motor, emotional, and cognitive function.

Among other uses, neuropsychological assessments can help identify depression in patients with neurologic impairment, determine the diagnosis and plan of care for patients with concussions, determine the risk of a motor vehicle crash in patients with cognitive impairment, and distinguish Alzheimer disease from vascular dementia.⁸ Components of such assessments include the Beck Anxiety Inventory (BAI) to assess anxiety, the Dementia Rating Scale-2 and Neuropsychological Assessment Battery-Screening Module to assess dementia, and the Beck Depression Inventory (BDI) to assess depression.⁹

EVALUATION Continued cognitive decline

A different psychologist performs the neuro­psychological assessment, who conducts the Repeatable Battery for the Assessment of Neuropsychological Status Update to determine if Ms. X is experiencing cognitive impairment. Her immediate memory, visuospatial/constructions, language, attention, and delayed memory are significantly impaired for someone her age. The psychologist also administers the Wechsler Adult Intelligence Scale IV and finds Ms. X’s general cognitive ability is within the low average range of intellectual functioning as measured by Full-Scale IQ. Ms. X scores 29 on the BDI-II, indicating significant depressive symptoms, and 13 on the BAI, indicating mild anxiety symptoms.

Ms. X is diagnosed with MDD and an unspecified neurocognitive disorder. The psychologist recommends she start CBT to address her mood and anxiety symptoms.

Upon reviewing the results with Ms. X, the treatment team again recommends a brain MRI, CBC, CMP, and UA to rule out organic causes of her cognitive decline. Ms. X decides against the MRI and laboratory workup and elects to continue her present medication regimen and CBT.

Several weeks later, Ms. X’s family brings her to the emergency department (ED) for evaluation of worsening mood, decreased personal hygiene, increased irritability, and further cognitive decline. They report she is having an increasingly difficult time remembering things such as where she parked her car. The ED team decides to discontinue clonazepam but continues sertraline and trazodone.

Continue to: CBC, CMP, and UA...

CBC, CMP, and UA are unremarkable. Ms. X undergoes a brain CT scan without contrast, which reveals hyperdense lesions in the inferior left tentorium, posterior fossa. A subsequent brain MRI with contrast reveals a dural-based enhancing mass, inferior to the left tentorium, in the left posterior fossa measuring 2.2 cm x 2.1 cm, suggestive of a meningioma. The team orders a Neurosurgery consult.

[polldaddy:12189571]

The authors’ observations

While most brain tumors are secondary to metastasis, meningiomas are the most common primary CNS tumor. Typically, they are asymptomatic; their diagnosis is often delayed until the patient presents with psychiatric symptoms without any focal neurologic findings. The frontal lobe is the most common location of meningioma. Data from 48 case reports of patients with meningiomas and psychiatric symptoms suggest symptoms do not always correlate with specific brain regions.^10,11

Indications for neuroimaging in cases such as Ms. X include an abrupt change in behavior or personality, lack of response to psychiatric treatment, presence of focal neurologic signs, and an unusual psychiatric presentation and development of symptoms.¹¹

TREATMENT Neurosurgery

Neurosurgery recommends and performs a suboccipital craniotomy for biopsy and resection. Ms. X tolerates the procedure well. A meningioma is found in the posterior fossa, near the cerebellar convexity. A biopsy finds no evidence of malignancies.

At her postoperative follow-up appointment several days after the procedure, Ms. X reports new-onset hearing loss and tinnitus.

[polldaddy:12189747]

Continue to: The authors' observations

Patients who require neurosurgery typically already carry a heavy psychiatric burden, which makes it challenging to determine the exact psychiatric consequences of neuro­surgery.^12-14 For example, research shows that temporal lobe resection and temporal lobectomy for treatment-resistant epilepsy can lead to an exacerbation of baseline psychiatric symptoms and the development of new symptoms (31% to 34%).^15,16 However, Bommakanti et al¹³ found no new psychiatric symptoms after resection of meningiomas, and surgery seemed to play a role in ameliorating psychiatric symptoms in patients with intracranial tumors. Research attempting to document the psychiatric sequelae of neurosurgery has had mixed results, and it is difficult to determine what effects brain surgery has on mental health.

OUTCOME Minimal improvement

Several weeks after neurosurgery, Ms. X and her family report her mood is improved. Her PHQ-9 score improves to 15, but her GAD-7 score increases to 13, 1 point above her previous score.

The treatment team recommends Ms. X continue taking sertraline 50 mg/d and trazodone 50 mg/d at bedtime. Ms. X’s family reports her cognition and memory have not improved; her MoCA score increases by 1 point to 23. The treatment team discusses with Ms. X and her family the possibility that her cognitive problems maybe better explained as a neurocognitive disorder rather than as a result of the meningioma, since her MoCA score has not significantly improved. Ms. X and her family decide to seek a second opinion from a neurologist.

Bottom Line

Pseudodementia is a term used to describe older adults who present with cognitive issues in the context of depressive symptoms. Even in the absence of focal findings, neuroimaging should be considered as part of the workup in patients who continue to experience a progressive decline in mood and cognitive function.

Related Resources

• Moller MD, Parmenter BA, Lane DW. Neuropsychological testing: a useful but underutilized resource. Current Psychiatry. 2019;18(11):40-46,51.
• Pollak J. Psychological/neuropsychological testing: when to refer for reexamination. Current Psychiatry. 2021;20(9):18- 19,30-31,37. doi:10.12788/cp.0157

Drug Brand Names

Citalopram • Celexa
Clonazepam • Klonopin
Duloxetine • Cymbalta
Fluoxetine • Prozac
Sertraline • Zoloft
Trazodone • Oleptro
Venlafaxine extended- release • Effexor XR

CASE Depressed and anxious

Five years ago, Ms. X, age 60, was diagnosed with treatment-resistant major depressive disorder (MDD) with anxiety. This diagnosis was established by a previous psychiatrist. She presents to a clinic for a second opinion.

Since her diagnosis, Ms. X has experienced sad mood, anhedonia, difficulty falling asleep, increased appetite and weight, and decreased concentration and attention. Her anxiety stems from her inability to work, which causes her to worry about her children. In the clinic, the treatment team conducts the Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder-7 item scale (GAD-7) with Ms. X. She scores 16 on the PHQ-9, indicating moderately severe depression, and scores 12 on the GAD-7, indicating moderate anxiety.

Ms. X’s current medication regimen consists of venlafaxine extended-release (XR) 225 mg/d, trazodone 100 mg/d at bedtime, and clonazepam 1 mg twice daily. She reports no significant improvement of her symptoms from these medications. Additionally, Ms. X reports that in the past she had been prescribed fluoxetine, citalopram, and duloxetine, but she cannot recall the dosages.

Ms. X appears appropriately groomed, maintains appropriate eye contact, has clear speech, and does not show evidence of internal stimulation; however, she has difficulty following instructions. She makes negative comments about herself such as “I’m worthless” and “Nobody cares about me.” The treatment team decides to taper Ms. X off venlafaxine XR and initiates sertraline 50 mg/d, while continuing trazodone 50 mg/d at bedtime and clonazepam 1 mg twice daily. The team refers her for cognitive-behavioral therapy (CBT) to address her cognitive distortions, sad mood, and anxiety. Ms. X is asked to follow up with Psychiatry in 1 week.

EVALUATION Unusual behavior

At her CBT intake, Ms. X endorses depression and anxiety. Her PHQ-9 score at this visit is 19 (moderately severe depression) and GAD-7 score is 16 (severe anxiety). The psychologist notes that Ms. X is able to complete activities of daily living and instrumental activities of daily living without assistance. Ms. X denies any use of illicit substances or alcohol. No gross memory impairment is noted during this appointment, though Ms. X exhibits unusual behavior, including exiting and re-entering the clinic multiple times to repeatedly ask about follow-up appointments. The psychologist concludes that Ms. X’s presentation and behavior can be explained by MDD and pseudodementia.

[polldaddy:12189562]

The authors’ observations

Pseudodementia gained recognition in clinical research >100 years ago.¹ Officially coined by Kiloh in 1961, the term was used broadly to categorize psychiatric cases that present like dementia but are the result of reversible causes. More recently, it has been used to describe older adults who present with cognitive deficits in the context of depressive symptoms.² The goal of evaluation is to determine if the primary issue is a cognitive disorder or a depressive episode. DSM-5-TR does not classify pseudodementia as a distinct diagnosis, but instead categorizes its symptoms as components under other major diagnostic categories. Patients can present with MDD and associated cognitive symptoms, or with a cognitive disorder with depressive symptoms, which would be diagnosed as a cognitive disorder with a major depressive-like episode.³

Pseudodementia is rare. Brodaty et al⁴ found the prevalence of pseudodementia in primary care settings was 0.6%. Older adults (age >65) who live alone are at increased risk of developing pseudodementia, which can be worsened by poor social support and acute psychosocial and environmental changes.⁵ A key characteristic of this disorder is that as the patient’s depressed mood improves, their memory and cognition also improve.⁶Table 1^3,6 outlines overlapping features of MDD and pseudodementia.

Continue to: EVALUATION Worsening depression

At her Psychiatry follow-up appointment, Ms. X reports that her mood is worse since she ended the relationship with her partner and she feels anxious because the partner was financially supporting her. Her PHQ-9 score is 24 (severe depression) and her GAD-7 score is 12 (moderate anxiety). Ms. X reports tolerating her transition from venlafaxine XR 225 mg/d to sertraline 50 mg/d well.

Additionally, Ms. X reports her children have called her “useless” since she continues to have difficulties following through on household tasks, even though she has no physical impairments that prevent her from completing them. The Psychiatry team observes that Ms. X has no problems walking or moving her arms or legs.

The Psychiatry team administers the Montreal Cognitive Assessment (MoCA). Ms. X scores 22, indicating mild impairment.

The team recommends a neuropsychological assessment to determine if this MoCA score is due to a cognitive disorder or is rooted in her mood symptoms. The team also recommends an MRI of the brain, complete blood count (CBC), comprehensive metabolic panel (CMP), and urinalysis (UA).

[polldaddy:12189567]

Continue to: The authors' observations

Neuropsychological assessments are important tools for exploring the behavioral manifestations of brain dysfunction (Table 2).⁷ These assessments factor in elements of neurology, psychiatry, and psychology to provide information about the diagnosis, prognosis, and functional status of patients with medical conditions, especially those with neurocognitive and psychiatric disorders. They combine information from the patient and collateral interviews, behavioral observations, a review of patient records, and objective tests of motor, emotional, and cognitive function.

Among other uses, neuropsychological assessments can help identify depression in patients with neurologic impairment, determine the diagnosis and plan of care for patients with concussions, determine the risk of a motor vehicle crash in patients with cognitive impairment, and distinguish Alzheimer disease from vascular dementia.⁸ Components of such assessments include the Beck Anxiety Inventory (BAI) to assess anxiety, the Dementia Rating Scale-2 and Neuropsychological Assessment Battery-Screening Module to assess dementia, and the Beck Depression Inventory (BDI) to assess depression.⁹

EVALUATION Continued cognitive decline

A different psychologist performs the neuro­psychological assessment, who conducts the Repeatable Battery for the Assessment of Neuropsychological Status Update to determine if Ms. X is experiencing cognitive impairment. Her immediate memory, visuospatial/constructions, language, attention, and delayed memory are significantly impaired for someone her age. The psychologist also administers the Wechsler Adult Intelligence Scale IV and finds Ms. X’s general cognitive ability is within the low average range of intellectual functioning as measured by Full-Scale IQ. Ms. X scores 29 on the BDI-II, indicating significant depressive symptoms, and 13 on the BAI, indicating mild anxiety symptoms.

Ms. X is diagnosed with MDD and an unspecified neurocognitive disorder. The psychologist recommends she start CBT to address her mood and anxiety symptoms.

Upon reviewing the results with Ms. X, the treatment team again recommends a brain MRI, CBC, CMP, and UA to rule out organic causes of her cognitive decline. Ms. X decides against the MRI and laboratory workup and elects to continue her present medication regimen and CBT.

Several weeks later, Ms. X’s family brings her to the emergency department (ED) for evaluation of worsening mood, decreased personal hygiene, increased irritability, and further cognitive decline. They report she is having an increasingly difficult time remembering things such as where she parked her car. The ED team decides to discontinue clonazepam but continues sertraline and trazodone.

Continue to: CBC, CMP, and UA...

CBC, CMP, and UA are unremarkable. Ms. X undergoes a brain CT scan without contrast, which reveals hyperdense lesions in the inferior left tentorium, posterior fossa. A subsequent brain MRI with contrast reveals a dural-based enhancing mass, inferior to the left tentorium, in the left posterior fossa measuring 2.2 cm x 2.1 cm, suggestive of a meningioma. The team orders a Neurosurgery consult.

[polldaddy:12189571]

The authors’ observations

While most brain tumors are secondary to metastasis, meningiomas are the most common primary CNS tumor. Typically, they are asymptomatic; their diagnosis is often delayed until the patient presents with psychiatric symptoms without any focal neurologic findings. The frontal lobe is the most common location of meningioma. Data from 48 case reports of patients with meningiomas and psychiatric symptoms suggest symptoms do not always correlate with specific brain regions.^10,11

Indications for neuroimaging in cases such as Ms. X include an abrupt change in behavior or personality, lack of response to psychiatric treatment, presence of focal neurologic signs, and an unusual psychiatric presentation and development of symptoms.¹¹

TREATMENT Neurosurgery

Neurosurgery recommends and performs a suboccipital craniotomy for biopsy and resection. Ms. X tolerates the procedure well. A meningioma is found in the posterior fossa, near the cerebellar convexity. A biopsy finds no evidence of malignancies.

At her postoperative follow-up appointment several days after the procedure, Ms. X reports new-onset hearing loss and tinnitus.

[polldaddy:12189747]

Continue to: The authors' observations

Patients who require neurosurgery typically already carry a heavy psychiatric burden, which makes it challenging to determine the exact psychiatric consequences of neuro­surgery.^12-14 For example, research shows that temporal lobe resection and temporal lobectomy for treatment-resistant epilepsy can lead to an exacerbation of baseline psychiatric symptoms and the development of new symptoms (31% to 34%).^15,16 However, Bommakanti et al¹³ found no new psychiatric symptoms after resection of meningiomas, and surgery seemed to play a role in ameliorating psychiatric symptoms in patients with intracranial tumors. Research attempting to document the psychiatric sequelae of neurosurgery has had mixed results, and it is difficult to determine what effects brain surgery has on mental health.

OUTCOME Minimal improvement

Several weeks after neurosurgery, Ms. X and her family report her mood is improved. Her PHQ-9 score improves to 15, but her GAD-7 score increases to 13, 1 point above her previous score.

The treatment team recommends Ms. X continue taking sertraline 50 mg/d and trazodone 50 mg/d at bedtime. Ms. X’s family reports her cognition and memory have not improved; her MoCA score increases by 1 point to 23. The treatment team discusses with Ms. X and her family the possibility that her cognitive problems maybe better explained as a neurocognitive disorder rather than as a result of the meningioma, since her MoCA score has not significantly improved. Ms. X and her family decide to seek a second opinion from a neurologist.

Bottom Line

Pseudodementia is a term used to describe older adults who present with cognitive issues in the context of depressive symptoms. Even in the absence of focal findings, neuroimaging should be considered as part of the workup in patients who continue to experience a progressive decline in mood and cognitive function.

Related Resources

• Moller MD, Parmenter BA, Lane DW. Neuropsychological testing: a useful but underutilized resource. Current Psychiatry. 2019;18(11):40-46,51.
• Pollak J. Psychological/neuropsychological testing: when to refer for reexamination. Current Psychiatry. 2021;20(9):18- 19,30-31,37. doi:10.12788/cp.0157

Drug Brand Names

Citalopram • Celexa
Clonazepam • Klonopin
Duloxetine • Cymbalta
Fluoxetine • Prozac
Sertraline • Zoloft
Trazodone • Oleptro
Venlafaxine extended- release • Effexor XR

Everyone’s memory fades to some extent as we age, but not everyone will develop Alzheimer’s disease. Screening the most likely people to develop Alzheimer’s remains an ongoing challenge, as some people present only unambiguous symptoms once their disease is advanced.

A new study in JAMA Network Open suggests that one early clue is found in people’s own self-perception of their memory skills. People who are more aware of their own declining memory capacity are less likely to develop Alzheimer’s, the study suggests.

“Some people are very aware of changes in their memory, but many people are unaware,” said study author Patrizia Vannini, PhD, a neurologist at Brigham and Women’s Hospital in Boston. There are gradations of unawareness of memory loss, Dr. Vannini said, from complete unawareness that anything is wrong, to a partial unawareness that memory is declining.

The study compared the records of 436 participants in the Alzheimer’s Disease Neuroimaging Initiative, an Alzheimer’s research institute housed at the University of Southern California. More than 90% of the participants were White, and generally had a college education. Their average age was 75 years, and 53% of participants were women.

Dr. Vannini and colleagues tracked people whose cognitive function was normal at the beginning of the study, based on the Clinical Dementia Rating. Throughout the course of the study, which included data from 2010 to 2021, 91 of the 436 participants experienced a sustained decline in their Clinical Dementia Rating scores, indicating a risk for eventual Alzheimer’s, whereas the other participants held steady.

The people who declined in cognitive function were less aware of slips in their memory, as assessed by discrepancies between people’s self-reports of their own memory skills and the perceptions of someone in their lives. For this part of the study, Dr. Vannini and colleagues used the Everyday Cognition Questionnaire, which evaluates memory tasks such as shopping without a grocery list or recalling conversations from a few days ago. Both the participant and the study partner rated their performance on such tasks compared to 10 years earlier. Those who were less aware of their memory slips were more likely to experience declines in the Clinical Dementia Rating, compared with people with a heightened concern about memory loss (as measured by being more concerned about memory decline than their study partners).

“Partial or complete unawareness is often related to delayed diagnosis of Alzheimer’s, because the patient is unaware they are having problems,” Dr. Vannini said, adding that this is associated with a poorer prognosis as well.
 

Implications for clinicians

Soo Borson, MD, professor of clinical family medicine at the University of Southern California and coleader of a CDC-funded early dementia detection center at New York University, pointed out that sometimes people are genuinely unaware that their memory is declining, while at other times they know it all too well but say everything is fine when a doctor asks about their current memory status. That may be because people fear the label of “Alzheimer’s,” Dr. Borson suggested, or simply because they don’t want to start a protracted diagnostic pathway that could involve lots of tests and time.

Dr. Borson, who was not involved in the study, noted that the population was predominantly White and well-educated, and by definition included people who were concerned enough about potential memory loss to become part of an Alzheimer’s research network. This limits the generalizability of this study’s results to other populations, Dr. Borson said.

Despite that limitation, in Dr. Borson’s view the study points to the continued importance of clinicians (ideally a primary care doctor who knows the patient well) engaging with patients about their brain health once they reach midlife. A doctor could ask if patients have noticed a decline in their thinking or memory over the last year, for example, or a more open-ended question about any memory concerns.

Although some patients may choose to withhold concerns about their memory, Dr. Borson acknowledged, the overall thrust of these questions is to provide a safe space for patients to air their concerns if they so choose. In some cases it would be appropriate to do a simple memory test on the spot, and then proceed accordingly – either for further tests if something of concern emerges, or to reassure the patient if the test doesn’t yield anything of note. In the latter case some patients will still want further tests for additional reassurance, and Dr. Borson thinks doctors should facilitate that request even if in their own judgment nothing is wrong.

“This is not like testing for impaired kidney function by doing a serum creatinine test,” Dr. Borson said. While the orientation of the health care system is toward quick and easy answers for everything, detecting possible dementia eludes such an approach.

Dr. Vannini reports funding from the National Institutes of Health National Institute on Aging. Dr. Borson reported no disclosures.

Everyone’s memory fades to some extent as we age, but not everyone will develop Alzheimer’s disease. Screening the most likely people to develop Alzheimer’s remains an ongoing challenge, as some people present only unambiguous symptoms once their disease is advanced.

A new study in JAMA Network Open suggests that one early clue is found in people’s own self-perception of their memory skills. People who are more aware of their own declining memory capacity are less likely to develop Alzheimer’s, the study suggests.

“Some people are very aware of changes in their memory, but many people are unaware,” said study author Patrizia Vannini, PhD, a neurologist at Brigham and Women’s Hospital in Boston. There are gradations of unawareness of memory loss, Dr. Vannini said, from complete unawareness that anything is wrong, to a partial unawareness that memory is declining.

The study compared the records of 436 participants in the Alzheimer’s Disease Neuroimaging Initiative, an Alzheimer’s research institute housed at the University of Southern California. More than 90% of the participants were White, and generally had a college education. Their average age was 75 years, and 53% of participants were women.

Dr. Vannini and colleagues tracked people whose cognitive function was normal at the beginning of the study, based on the Clinical Dementia Rating. Throughout the course of the study, which included data from 2010 to 2021, 91 of the 436 participants experienced a sustained decline in their Clinical Dementia Rating scores, indicating a risk for eventual Alzheimer’s, whereas the other participants held steady.

The people who declined in cognitive function were less aware of slips in their memory, as assessed by discrepancies between people’s self-reports of their own memory skills and the perceptions of someone in their lives. For this part of the study, Dr. Vannini and colleagues used the Everyday Cognition Questionnaire, which evaluates memory tasks such as shopping without a grocery list or recalling conversations from a few days ago. Both the participant and the study partner rated their performance on such tasks compared to 10 years earlier. Those who were less aware of their memory slips were more likely to experience declines in the Clinical Dementia Rating, compared with people with a heightened concern about memory loss (as measured by being more concerned about memory decline than their study partners).

“Partial or complete unawareness is often related to delayed diagnosis of Alzheimer’s, because the patient is unaware they are having problems,” Dr. Vannini said, adding that this is associated with a poorer prognosis as well.
 

Implications for clinicians

Soo Borson, MD, professor of clinical family medicine at the University of Southern California and coleader of a CDC-funded early dementia detection center at New York University, pointed out that sometimes people are genuinely unaware that their memory is declining, while at other times they know it all too well but say everything is fine when a doctor asks about their current memory status. That may be because people fear the label of “Alzheimer’s,” Dr. Borson suggested, or simply because they don’t want to start a protracted diagnostic pathway that could involve lots of tests and time.

Dr. Borson, who was not involved in the study, noted that the population was predominantly White and well-educated, and by definition included people who were concerned enough about potential memory loss to become part of an Alzheimer’s research network. This limits the generalizability of this study’s results to other populations, Dr. Borson said.

Despite that limitation, in Dr. Borson’s view the study points to the continued importance of clinicians (ideally a primary care doctor who knows the patient well) engaging with patients about their brain health once they reach midlife. A doctor could ask if patients have noticed a decline in their thinking or memory over the last year, for example, or a more open-ended question about any memory concerns.

Although some patients may choose to withhold concerns about their memory, Dr. Borson acknowledged, the overall thrust of these questions is to provide a safe space for patients to air their concerns if they so choose. In some cases it would be appropriate to do a simple memory test on the spot, and then proceed accordingly – either for further tests if something of concern emerges, or to reassure the patient if the test doesn’t yield anything of note. In the latter case some patients will still want further tests for additional reassurance, and Dr. Borson thinks doctors should facilitate that request even if in their own judgment nothing is wrong.

“This is not like testing for impaired kidney function by doing a serum creatinine test,” Dr. Borson said. While the orientation of the health care system is toward quick and easy answers for everything, detecting possible dementia eludes such an approach.

Dr. Vannini reports funding from the National Institutes of Health National Institute on Aging. Dr. Borson reported no disclosures.

Everyone’s memory fades to some extent as we age, but not everyone will develop Alzheimer’s disease. Screening the most likely people to develop Alzheimer’s remains an ongoing challenge, as some people present only unambiguous symptoms once their disease is advanced.

A new study in JAMA Network Open suggests that one early clue is found in people’s own self-perception of their memory skills. People who are more aware of their own declining memory capacity are less likely to develop Alzheimer’s, the study suggests.

“Some people are very aware of changes in their memory, but many people are unaware,” said study author Patrizia Vannini, PhD, a neurologist at Brigham and Women’s Hospital in Boston. There are gradations of unawareness of memory loss, Dr. Vannini said, from complete unawareness that anything is wrong, to a partial unawareness that memory is declining.

The study compared the records of 436 participants in the Alzheimer’s Disease Neuroimaging Initiative, an Alzheimer’s research institute housed at the University of Southern California. More than 90% of the participants were White, and generally had a college education. Their average age was 75 years, and 53% of participants were women.

Dr. Vannini and colleagues tracked people whose cognitive function was normal at the beginning of the study, based on the Clinical Dementia Rating. Throughout the course of the study, which included data from 2010 to 2021, 91 of the 436 participants experienced a sustained decline in their Clinical Dementia Rating scores, indicating a risk for eventual Alzheimer’s, whereas the other participants held steady.

The people who declined in cognitive function were less aware of slips in their memory, as assessed by discrepancies between people’s self-reports of their own memory skills and the perceptions of someone in their lives. For this part of the study, Dr. Vannini and colleagues used the Everyday Cognition Questionnaire, which evaluates memory tasks such as shopping without a grocery list or recalling conversations from a few days ago. Both the participant and the study partner rated their performance on such tasks compared to 10 years earlier. Those who were less aware of their memory slips were more likely to experience declines in the Clinical Dementia Rating, compared with people with a heightened concern about memory loss (as measured by being more concerned about memory decline than their study partners).

“Partial or complete unawareness is often related to delayed diagnosis of Alzheimer’s, because the patient is unaware they are having problems,” Dr. Vannini said, adding that this is associated with a poorer prognosis as well.
 

Implications for clinicians

Soo Borson, MD, professor of clinical family medicine at the University of Southern California and coleader of a CDC-funded early dementia detection center at New York University, pointed out that sometimes people are genuinely unaware that their memory is declining, while at other times they know it all too well but say everything is fine when a doctor asks about their current memory status. That may be because people fear the label of “Alzheimer’s,” Dr. Borson suggested, or simply because they don’t want to start a protracted diagnostic pathway that could involve lots of tests and time.

Dr. Borson, who was not involved in the study, noted that the population was predominantly White and well-educated, and by definition included people who were concerned enough about potential memory loss to become part of an Alzheimer’s research network. This limits the generalizability of this study’s results to other populations, Dr. Borson said.

Despite that limitation, in Dr. Borson’s view the study points to the continued importance of clinicians (ideally a primary care doctor who knows the patient well) engaging with patients about their brain health once they reach midlife. A doctor could ask if patients have noticed a decline in their thinking or memory over the last year, for example, or a more open-ended question about any memory concerns.

Although some patients may choose to withhold concerns about their memory, Dr. Borson acknowledged, the overall thrust of these questions is to provide a safe space for patients to air their concerns if they so choose. In some cases it would be appropriate to do a simple memory test on the spot, and then proceed accordingly – either for further tests if something of concern emerges, or to reassure the patient if the test doesn’t yield anything of note. In the latter case some patients will still want further tests for additional reassurance, and Dr. Borson thinks doctors should facilitate that request even if in their own judgment nothing is wrong.

“This is not like testing for impaired kidney function by doing a serum creatinine test,” Dr. Borson said. While the orientation of the health care system is toward quick and easy answers for everything, detecting possible dementia eludes such an approach.

Dr. Vannini reports funding from the National Institutes of Health National Institute on Aging. Dr. Borson reported no disclosures.

Walnuts have been associated with better cognitive development and psychological maturation in teens, new research shows. Adolescents who consumed walnuts for at least 100 days showed improved sustained attention and fluid intelligence as well as a reduction in symptoms of attension deficit hyperactivity disorder, compared with matched controls who did not consume the nuts. However, there were no statistically significant changes between the groups in other parameters, such as working memory and executive function.

Clinicians should advise adolescents “to eat a handful of walnuts three times a week for the rest of their lives. They may have a healthier brain with better cognitive function,” said senior investigator Jordi Julvez, PhD, group leader at the Institute of Health Research Pere Virgili, Barcelona, and associated researcher at the Barcelona Institute for Global Health.

The study was published online in eClinicalMedicine.
 

Rich source of omega-3s

Adolescence is “a period of refinement of brain connectivity and complex behaviors,” the investigators noted.  

Previous research suggests polyunsaturated fatty acids are key in central nervous system architecture and function during times of neural development, with three specific PUFAs playing an “essential developmental role.”

Two omega-3 fatty acids – docosahexaenoic acid and eicosapentaenoic acid – are PUFAs that must be obtained through diet, mainly from seafood. Walnuts are “among the richest sources” of plant-derived omega-3 fatty acids, particularly alpha-linolenic acid (ALA), a precursor for longer-chain EPA and DHA.

ALA independently “has positive effects on brain function and plasticity,” the authors wrote. In addition, walnut constituents – particularly polyphenols and other bioactive compounds – “may act synergistically with ALA to foster brain health.”

Earlier small studies have found positive associations between walnut consumption and cognitive function in children, adolescents, and young adults, but to date, no randomized controlled trial has focused on the effect of walnut consumption on adolescent neuropsychological function.

The researchers studied 771 healthy adolescents (aged 11-16 years, mean age 14) drawn from 12 Spanish high schools. Participants were instructed to follow healthy eating recommendations and were randomly assigned 1:1 to the intervention (n = 386) or the control group (n = 385).

At baseline and after 6 months, they completed neuropsychological tests and behavioral rating scales. The Attention Network Test assessed attention, and the N-back test was used to assess working memory. The Tests of Primary Mental Abilities assessed fluid intelligence. Risky decision-making was tested using the Roulettes Task.
 

Fruit and nuts

Participants also completed the Strengths and Difficulties Questionnaire, which provided a total score of problem behavior. Teachers filled out the ADHD DSM-IV form list to provide additional information about ADHD behaviors.

The intervention group received 30 grams/day of raw California walnut kernels to incorporate into their daily diet. It is estimated that this walnut contains about 9 g of ALA per 100 g.

All participants received a seasonal fruit calendar and were asked to eat at least one piece of seasonal fruit daily.

Parents reported their child’s daily walnut consumption, with adherence defined as 100 or more days of eating walnuts during the 6-month period.

All main analyses were based on an intention-to-treat method (participants were analyzed according to their original group assignment, regardless of their adherence to the intervention).

The researchers also conducted a secondary per-protocol analysis, comparing the intervention and control groups to estimate the effect if all participants had adhered to their assigned intervention. They censored data for participants who reported eating walnuts for less than 100 days during the 6-month trial period.

Secondary outcomes included changes in height, weight, waist circumference, and BMI, as well as red blood cell proportions of omega-3 fatty acids (DHA, EPA, and ALA) at baseline and after 6 months.
 

Adherence counts

Most participants had “medium” or “high” levels of adherence to the Mediterranean diet, with “no meaningful differences” at baseline between the intervention and control groups in lifestyle characteristics or mean scores in all primary endpoints.

In the ITT analysis, there were no statistically significant differences in primary outcomes between the groups following the intervention. As for secondary outcomes, the RBC ALA significantly increased in the walnuts group but not the control group (coefficient, 0.04%; 95% confidence interval, 0.03%-0.06%; P < .0001).

However, there were differences in primary outcomes between the groups in the per-protocol analysis: The adherence-adjusted effect on improvement in attention score was −11.26 ms; 95% CI, −19.92 to −2.60; P = .011) for the intervention versus the control group.

The per-protocol analysis showed other differences: an improvement in fluid intelligence score (1.78; 95% CI, 0.90 - 2.67; P < .0001) and a reduction in ADHD symptom score (−2.18; 95% CI, −3.70 to −0.67; P = .0050).

“Overall, no significant differences were found in the intervention group in relation to the control group,” Dr. Julvez said in a news release. “But if the adherence factor is considered, then positive results are observed, since participants who most closely followed the guidelines – in terms of the recommended dose of walnuts and the number of days of consumption – did show improvements in the neuropsychological functions evaluated.”

Adolescence “is a time of great biological changes. Hormonal transformation occurs, which in turn is responsible for stimulating the synaptic growth of the frontal lobe,” he continued, adding that this brain region “enables neuropsychological maturation of more complex emotional and cognitive functions.”

“Neurons that are well nourished with these types of fatty acids will be able to grow and form new, stronger synapses,” he said.
 

Food as medicine

Uma Naidoo, MD, director of nutritional and lifestyle psychiatry at Massachusetts General Hospital, Boston, “commends” the researchers for conducting an RCT with a “robust” sample size and said she is “excited to see research like this furthering functional nutrition for mental health,” as she believes that “food is medicine.”

Dr. Naidoo, a professional chef, nutritional biologist, and author of the book “This Is Your Brain on Food,” said the findings “align” with her own approach to nutritional psychiatry and are also “in line” with her clinical practice.

However, although these results are “promising,” more research is needed across more diverse populations to “make sure these results are truly generalizable,” said Dr. Naidoo, a faculty member at Harvard Medical School, Boston, who was not involved with the study.

She “envisions a future where the research is so advanced that we can ‘dose’ these healthy whole foods for specific psychiatric symptoms and conditions.”

This study was supported by Instituto de Salud Carlos III (co-funded by European Union Regional Development Fund “A way to make Europe”). The California Walnut Commission has given support by supplying the walnuts for free for the Walnuts Smart Snack Dietary Intervention Trial. Dr. Julvez holds a Miguel Servet-II contract awarded by the Instituto de Salud Carlos III (co-funded by European Union Social Fund). The other authors’ disclosures are listed in the original article. Dr. Naidoo reports no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Walnuts have been associated with better cognitive development and psychological maturation in teens, new research shows. Adolescents who consumed walnuts for at least 100 days showed improved sustained attention and fluid intelligence as well as a reduction in symptoms of attension deficit hyperactivity disorder, compared with matched controls who did not consume the nuts. However, there were no statistically significant changes between the groups in other parameters, such as working memory and executive function.

Clinicians should advise adolescents “to eat a handful of walnuts three times a week for the rest of their lives. They may have a healthier brain with better cognitive function,” said senior investigator Jordi Julvez, PhD, group leader at the Institute of Health Research Pere Virgili, Barcelona, and associated researcher at the Barcelona Institute for Global Health.

The study was published online in eClinicalMedicine.
 

Rich source of omega-3s

Adolescence is “a period of refinement of brain connectivity and complex behaviors,” the investigators noted.  

Previous research suggests polyunsaturated fatty acids are key in central nervous system architecture and function during times of neural development, with three specific PUFAs playing an “essential developmental role.”

Two omega-3 fatty acids – docosahexaenoic acid and eicosapentaenoic acid – are PUFAs that must be obtained through diet, mainly from seafood. Walnuts are “among the richest sources” of plant-derived omega-3 fatty acids, particularly alpha-linolenic acid (ALA), a precursor for longer-chain EPA and DHA.

ALA independently “has positive effects on brain function and plasticity,” the authors wrote. In addition, walnut constituents – particularly polyphenols and other bioactive compounds – “may act synergistically with ALA to foster brain health.”

Earlier small studies have found positive associations between walnut consumption and cognitive function in children, adolescents, and young adults, but to date, no randomized controlled trial has focused on the effect of walnut consumption on adolescent neuropsychological function.

The researchers studied 771 healthy adolescents (aged 11-16 years, mean age 14) drawn from 12 Spanish high schools. Participants were instructed to follow healthy eating recommendations and were randomly assigned 1:1 to the intervention (n = 386) or the control group (n = 385).

At baseline and after 6 months, they completed neuropsychological tests and behavioral rating scales. The Attention Network Test assessed attention, and the N-back test was used to assess working memory. The Tests of Primary Mental Abilities assessed fluid intelligence. Risky decision-making was tested using the Roulettes Task.
 

Fruit and nuts

Participants also completed the Strengths and Difficulties Questionnaire, which provided a total score of problem behavior. Teachers filled out the ADHD DSM-IV form list to provide additional information about ADHD behaviors.

The intervention group received 30 grams/day of raw California walnut kernels to incorporate into their daily diet. It is estimated that this walnut contains about 9 g of ALA per 100 g.

All participants received a seasonal fruit calendar and were asked to eat at least one piece of seasonal fruit daily.

Parents reported their child’s daily walnut consumption, with adherence defined as 100 or more days of eating walnuts during the 6-month period.

All main analyses were based on an intention-to-treat method (participants were analyzed according to their original group assignment, regardless of their adherence to the intervention).

The researchers also conducted a secondary per-protocol analysis, comparing the intervention and control groups to estimate the effect if all participants had adhered to their assigned intervention. They censored data for participants who reported eating walnuts for less than 100 days during the 6-month trial period.

Secondary outcomes included changes in height, weight, waist circumference, and BMI, as well as red blood cell proportions of omega-3 fatty acids (DHA, EPA, and ALA) at baseline and after 6 months.
 

Adherence counts

Most participants had “medium” or “high” levels of adherence to the Mediterranean diet, with “no meaningful differences” at baseline between the intervention and control groups in lifestyle characteristics or mean scores in all primary endpoints.

In the ITT analysis, there were no statistically significant differences in primary outcomes between the groups following the intervention. As for secondary outcomes, the RBC ALA significantly increased in the walnuts group but not the control group (coefficient, 0.04%; 95% confidence interval, 0.03%-0.06%; P < .0001).

However, there were differences in primary outcomes between the groups in the per-protocol analysis: The adherence-adjusted effect on improvement in attention score was −11.26 ms; 95% CI, −19.92 to −2.60; P = .011) for the intervention versus the control group.

The per-protocol analysis showed other differences: an improvement in fluid intelligence score (1.78; 95% CI, 0.90 - 2.67; P < .0001) and a reduction in ADHD symptom score (−2.18; 95% CI, −3.70 to −0.67; P = .0050).

“Overall, no significant differences were found in the intervention group in relation to the control group,” Dr. Julvez said in a news release. “But if the adherence factor is considered, then positive results are observed, since participants who most closely followed the guidelines – in terms of the recommended dose of walnuts and the number of days of consumption – did show improvements in the neuropsychological functions evaluated.”

Adolescence “is a time of great biological changes. Hormonal transformation occurs, which in turn is responsible for stimulating the synaptic growth of the frontal lobe,” he continued, adding that this brain region “enables neuropsychological maturation of more complex emotional and cognitive functions.”

“Neurons that are well nourished with these types of fatty acids will be able to grow and form new, stronger synapses,” he said.
 

Food as medicine

Uma Naidoo, MD, director of nutritional and lifestyle psychiatry at Massachusetts General Hospital, Boston, “commends” the researchers for conducting an RCT with a “robust” sample size and said she is “excited to see research like this furthering functional nutrition for mental health,” as she believes that “food is medicine.”

Dr. Naidoo, a professional chef, nutritional biologist, and author of the book “This Is Your Brain on Food,” said the findings “align” with her own approach to nutritional psychiatry and are also “in line” with her clinical practice.

However, although these results are “promising,” more research is needed across more diverse populations to “make sure these results are truly generalizable,” said Dr. Naidoo, a faculty member at Harvard Medical School, Boston, who was not involved with the study.

She “envisions a future where the research is so advanced that we can ‘dose’ these healthy whole foods for specific psychiatric symptoms and conditions.”

This study was supported by Instituto de Salud Carlos III (co-funded by European Union Regional Development Fund “A way to make Europe”). The California Walnut Commission has given support by supplying the walnuts for free for the Walnuts Smart Snack Dietary Intervention Trial. Dr. Julvez holds a Miguel Servet-II contract awarded by the Instituto de Salud Carlos III (co-funded by European Union Social Fund). The other authors’ disclosures are listed in the original article. Dr. Naidoo reports no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Walnuts have been associated with better cognitive development and psychological maturation in teens, new research shows. Adolescents who consumed walnuts for at least 100 days showed improved sustained attention and fluid intelligence as well as a reduction in symptoms of attension deficit hyperactivity disorder, compared with matched controls who did not consume the nuts. However, there were no statistically significant changes between the groups in other parameters, such as working memory and executive function.

Clinicians should advise adolescents “to eat a handful of walnuts three times a week for the rest of their lives. They may have a healthier brain with better cognitive function,” said senior investigator Jordi Julvez, PhD, group leader at the Institute of Health Research Pere Virgili, Barcelona, and associated researcher at the Barcelona Institute for Global Health.

The study was published online in eClinicalMedicine.
 

Rich source of omega-3s

Adolescence is “a period of refinement of brain connectivity and complex behaviors,” the investigators noted.  

Previous research suggests polyunsaturated fatty acids are key in central nervous system architecture and function during times of neural development, with three specific PUFAs playing an “essential developmental role.”

Two omega-3 fatty acids – docosahexaenoic acid and eicosapentaenoic acid – are PUFAs that must be obtained through diet, mainly from seafood. Walnuts are “among the richest sources” of plant-derived omega-3 fatty acids, particularly alpha-linolenic acid (ALA), a precursor for longer-chain EPA and DHA.

ALA independently “has positive effects on brain function and plasticity,” the authors wrote. In addition, walnut constituents – particularly polyphenols and other bioactive compounds – “may act synergistically with ALA to foster brain health.”

Earlier small studies have found positive associations between walnut consumption and cognitive function in children, adolescents, and young adults, but to date, no randomized controlled trial has focused on the effect of walnut consumption on adolescent neuropsychological function.

The researchers studied 771 healthy adolescents (aged 11-16 years, mean age 14) drawn from 12 Spanish high schools. Participants were instructed to follow healthy eating recommendations and were randomly assigned 1:1 to the intervention (n = 386) or the control group (n = 385).

At baseline and after 6 months, they completed neuropsychological tests and behavioral rating scales. The Attention Network Test assessed attention, and the N-back test was used to assess working memory. The Tests of Primary Mental Abilities assessed fluid intelligence. Risky decision-making was tested using the Roulettes Task.
 

Fruit and nuts

Participants also completed the Strengths and Difficulties Questionnaire, which provided a total score of problem behavior. Teachers filled out the ADHD DSM-IV form list to provide additional information about ADHD behaviors.

The intervention group received 30 grams/day of raw California walnut kernels to incorporate into their daily diet. It is estimated that this walnut contains about 9 g of ALA per 100 g.

All participants received a seasonal fruit calendar and were asked to eat at least one piece of seasonal fruit daily.

Parents reported their child’s daily walnut consumption, with adherence defined as 100 or more days of eating walnuts during the 6-month period.

All main analyses were based on an intention-to-treat method (participants were analyzed according to their original group assignment, regardless of their adherence to the intervention).

The researchers also conducted a secondary per-protocol analysis, comparing the intervention and control groups to estimate the effect if all participants had adhered to their assigned intervention. They censored data for participants who reported eating walnuts for less than 100 days during the 6-month trial period.

Secondary outcomes included changes in height, weight, waist circumference, and BMI, as well as red blood cell proportions of omega-3 fatty acids (DHA, EPA, and ALA) at baseline and after 6 months.
 

Adherence counts

Most participants had “medium” or “high” levels of adherence to the Mediterranean diet, with “no meaningful differences” at baseline between the intervention and control groups in lifestyle characteristics or mean scores in all primary endpoints.

In the ITT analysis, there were no statistically significant differences in primary outcomes between the groups following the intervention. As for secondary outcomes, the RBC ALA significantly increased in the walnuts group but not the control group (coefficient, 0.04%; 95% confidence interval, 0.03%-0.06%; P < .0001).

However, there were differences in primary outcomes between the groups in the per-protocol analysis: The adherence-adjusted effect on improvement in attention score was −11.26 ms; 95% CI, −19.92 to −2.60; P = .011) for the intervention versus the control group.

The per-protocol analysis showed other differences: an improvement in fluid intelligence score (1.78; 95% CI, 0.90 - 2.67; P < .0001) and a reduction in ADHD symptom score (−2.18; 95% CI, −3.70 to −0.67; P = .0050).

“Overall, no significant differences were found in the intervention group in relation to the control group,” Dr. Julvez said in a news release. “But if the adherence factor is considered, then positive results are observed, since participants who most closely followed the guidelines – in terms of the recommended dose of walnuts and the number of days of consumption – did show improvements in the neuropsychological functions evaluated.”

Adolescence “is a time of great biological changes. Hormonal transformation occurs, which in turn is responsible for stimulating the synaptic growth of the frontal lobe,” he continued, adding that this brain region “enables neuropsychological maturation of more complex emotional and cognitive functions.”

“Neurons that are well nourished with these types of fatty acids will be able to grow and form new, stronger synapses,” he said.
 

Food as medicine

Uma Naidoo, MD, director of nutritional and lifestyle psychiatry at Massachusetts General Hospital, Boston, “commends” the researchers for conducting an RCT with a “robust” sample size and said she is “excited to see research like this furthering functional nutrition for mental health,” as she believes that “food is medicine.”

Dr. Naidoo, a professional chef, nutritional biologist, and author of the book “This Is Your Brain on Food,” said the findings “align” with her own approach to nutritional psychiatry and are also “in line” with her clinical practice.

However, although these results are “promising,” more research is needed across more diverse populations to “make sure these results are truly generalizable,” said Dr. Naidoo, a faculty member at Harvard Medical School, Boston, who was not involved with the study.

She “envisions a future where the research is so advanced that we can ‘dose’ these healthy whole foods for specific psychiatric symptoms and conditions.”

This study was supported by Instituto de Salud Carlos III (co-funded by European Union Regional Development Fund “A way to make Europe”). The California Walnut Commission has given support by supplying the walnuts for free for the Walnuts Smart Snack Dietary Intervention Trial. Dr. Julvez holds a Miguel Servet-II contract awarded by the Instituto de Salud Carlos III (co-funded by European Union Social Fund). The other authors’ disclosures are listed in the original article. Dr. Naidoo reports no relevant financial relationships.

A version of this article first appeared on Medscape.com.

BOSTON – Treating atrial fibrillation with catheter ablation in addition to medical management may offer greater protection against cognitive impairment than medical management alone, new research suggests.

Investigators found adults who had previously undergone catheter ablation were significantly less likely to be cognitively impaired during the 2-year study period, compared with those who receive medical management alone.

“Catheter ablation is intended to stop atrial fibrillation and restore the normal rhythm of the heart. By doing so, there is an improved cerebral hemodynamic profile,” said Bahadar S. Srichawla, DO, department of neurology, University of Massachusetts, Worcester.

“Thus, long-term cognitive outcomes may be improved due to improved blood flow to the brain by restoring the normal rhythm of the heart,” he added.

This research was presented at the 2023 annual meeting of the American Academy of Neurology.
 

Heart-brain connection

The study involved 887 older adults (mean age 75; 49% women) with atrial fibrillation participating in the SAGE-AF (Systematic Assessment of Geriatric Elements) study. A total of 193 (22%) participants underwent catheter ablation prior to enrollment. These individuals more frequently had an implantable cardiac device (46% vs. 28%, P < .001) and persistent atrial fibrillation (31% vs. 23%, P < .05).

Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA) tool at baseline and 1 and 2 years, with cognitive impairment defined as a MoCA score of 23 or below. Individuals who had catheter ablation had an average MoCA score of 25, compared with an average score of 23 in those who didn’t have catheter ablation.

After adjusting for potential confounding factors such as heart disease, renal disease, sleep apnea, and atrial fibrillation risk score, those who underwent catheter ablation were 36% less likely to develop cognitive impairment over 2 years than those who were treated only with medication (adjusted odds ratio, 0.64; 95% CI, 0.46-0.88).

During his presentation, Dr. Srichawla noted there is a hypothesis that individuals who are anticoagulated with warfarin may be prone to cerebral microbleeds and may be more cognitively impaired over time.

However, in a subgroup analysis, “cognitive function was similar at 2-year follow-up in those anticoagulated with warfarin, compared with all other anticoagulants. However, it should be noted that in this study, a direct head-to-head comparison was not done,” Dr. Srichawla told attendees.

“In patients with atrial fibrillation, catheter ablation should be discussed as a potential treatment strategy, particularly in patients who have or are at risk for cognitive decline and dementia,” Dr. Srichawla said.
 

Intriguing findings

Commenting on the research, Percy Griffin, PhD, Alzheimer’s Association director of scientific engagement, said the study is “intriguing and adds to what we know from previous research connecting cardiovascular and cognitive health.”

“However, there are limitations to this study,” Dr. Griffin said, “including its predominantly White cohort and the use of only neuropsychiatric testing to diagnose dementia. More research is needed to fully understand the impact of atrial fibrillation on cognitive outcomes in all people.”

“It’s well known that the heart and the brain are intimately connected. Individuals experiencing any cardiovascular issues should speak to their doctor,” Dr. Griffin added.

Shaheen Lakhan, MD, PhD, a neurologist and researcher in Boston, agreed. “If you ever get up too quickly and feel woozy, that is your brain not getting enough blood flow and you are getting all the warning signs to correct that – or else! Similarly, with atrial fibrillation, the heart is contracting, but not effectively pumping blood to the brain,” he said.

“This line of research shows that correcting the abnormal heart rhythm by zapping the faulty circuit with a catheter is actually better for your brain health than just taking medications alone,” added Dr. Lakhan, who was not involved with the study.

The study had no commercial funding. Dr. Srichawla, Dr. Griffin, and Dr. Lakhan report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

BOSTON – Treating atrial fibrillation with catheter ablation in addition to medical management may offer greater protection against cognitive impairment than medical management alone, new research suggests.

Investigators found adults who had previously undergone catheter ablation were significantly less likely to be cognitively impaired during the 2-year study period, compared with those who receive medical management alone.

“Catheter ablation is intended to stop atrial fibrillation and restore the normal rhythm of the heart. By doing so, there is an improved cerebral hemodynamic profile,” said Bahadar S. Srichawla, DO, department of neurology, University of Massachusetts, Worcester.

“Thus, long-term cognitive outcomes may be improved due to improved blood flow to the brain by restoring the normal rhythm of the heart,” he added.

This research was presented at the 2023 annual meeting of the American Academy of Neurology.
 

Heart-brain connection

The study involved 887 older adults (mean age 75; 49% women) with atrial fibrillation participating in the SAGE-AF (Systematic Assessment of Geriatric Elements) study. A total of 193 (22%) participants underwent catheter ablation prior to enrollment. These individuals more frequently had an implantable cardiac device (46% vs. 28%, P < .001) and persistent atrial fibrillation (31% vs. 23%, P < .05).

Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA) tool at baseline and 1 and 2 years, with cognitive impairment defined as a MoCA score of 23 or below. Individuals who had catheter ablation had an average MoCA score of 25, compared with an average score of 23 in those who didn’t have catheter ablation.

After adjusting for potential confounding factors such as heart disease, renal disease, sleep apnea, and atrial fibrillation risk score, those who underwent catheter ablation were 36% less likely to develop cognitive impairment over 2 years than those who were treated only with medication (adjusted odds ratio, 0.64; 95% CI, 0.46-0.88).

During his presentation, Dr. Srichawla noted there is a hypothesis that individuals who are anticoagulated with warfarin may be prone to cerebral microbleeds and may be more cognitively impaired over time.

However, in a subgroup analysis, “cognitive function was similar at 2-year follow-up in those anticoagulated with warfarin, compared with all other anticoagulants. However, it should be noted that in this study, a direct head-to-head comparison was not done,” Dr. Srichawla told attendees.

“In patients with atrial fibrillation, catheter ablation should be discussed as a potential treatment strategy, particularly in patients who have or are at risk for cognitive decline and dementia,” Dr. Srichawla said.
 

Intriguing findings

Commenting on the research, Percy Griffin, PhD, Alzheimer’s Association director of scientific engagement, said the study is “intriguing and adds to what we know from previous research connecting cardiovascular and cognitive health.”

“However, there are limitations to this study,” Dr. Griffin said, “including its predominantly White cohort and the use of only neuropsychiatric testing to diagnose dementia. More research is needed to fully understand the impact of atrial fibrillation on cognitive outcomes in all people.”

“It’s well known that the heart and the brain are intimately connected. Individuals experiencing any cardiovascular issues should speak to their doctor,” Dr. Griffin added.

Shaheen Lakhan, MD, PhD, a neurologist and researcher in Boston, agreed. “If you ever get up too quickly and feel woozy, that is your brain not getting enough blood flow and you are getting all the warning signs to correct that – or else! Similarly, with atrial fibrillation, the heart is contracting, but not effectively pumping blood to the brain,” he said.

“This line of research shows that correcting the abnormal heart rhythm by zapping the faulty circuit with a catheter is actually better for your brain health than just taking medications alone,” added Dr. Lakhan, who was not involved with the study.

The study had no commercial funding. Dr. Srichawla, Dr. Griffin, and Dr. Lakhan report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

BOSTON – Treating atrial fibrillation with catheter ablation in addition to medical management may offer greater protection against cognitive impairment than medical management alone, new research suggests.

Investigators found adults who had previously undergone catheter ablation were significantly less likely to be cognitively impaired during the 2-year study period, compared with those who receive medical management alone.

“Catheter ablation is intended to stop atrial fibrillation and restore the normal rhythm of the heart. By doing so, there is an improved cerebral hemodynamic profile,” said Bahadar S. Srichawla, DO, department of neurology, University of Massachusetts, Worcester.

“Thus, long-term cognitive outcomes may be improved due to improved blood flow to the brain by restoring the normal rhythm of the heart,” he added.

This research was presented at the 2023 annual meeting of the American Academy of Neurology.
 

Heart-brain connection

The study involved 887 older adults (mean age 75; 49% women) with atrial fibrillation participating in the SAGE-AF (Systematic Assessment of Geriatric Elements) study. A total of 193 (22%) participants underwent catheter ablation prior to enrollment. These individuals more frequently had an implantable cardiac device (46% vs. 28%, P < .001) and persistent atrial fibrillation (31% vs. 23%, P < .05).

Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA) tool at baseline and 1 and 2 years, with cognitive impairment defined as a MoCA score of 23 or below. Individuals who had catheter ablation had an average MoCA score of 25, compared with an average score of 23 in those who didn’t have catheter ablation.

After adjusting for potential confounding factors such as heart disease, renal disease, sleep apnea, and atrial fibrillation risk score, those who underwent catheter ablation were 36% less likely to develop cognitive impairment over 2 years than those who were treated only with medication (adjusted odds ratio, 0.64; 95% CI, 0.46-0.88).

During his presentation, Dr. Srichawla noted there is a hypothesis that individuals who are anticoagulated with warfarin may be prone to cerebral microbleeds and may be more cognitively impaired over time.

However, in a subgroup analysis, “cognitive function was similar at 2-year follow-up in those anticoagulated with warfarin, compared with all other anticoagulants. However, it should be noted that in this study, a direct head-to-head comparison was not done,” Dr. Srichawla told attendees.

“In patients with atrial fibrillation, catheter ablation should be discussed as a potential treatment strategy, particularly in patients who have or are at risk for cognitive decline and dementia,” Dr. Srichawla said.
 

Intriguing findings

Commenting on the research, Percy Griffin, PhD, Alzheimer’s Association director of scientific engagement, said the study is “intriguing and adds to what we know from previous research connecting cardiovascular and cognitive health.”

“However, there are limitations to this study,” Dr. Griffin said, “including its predominantly White cohort and the use of only neuropsychiatric testing to diagnose dementia. More research is needed to fully understand the impact of atrial fibrillation on cognitive outcomes in all people.”

“It’s well known that the heart and the brain are intimately connected. Individuals experiencing any cardiovascular issues should speak to their doctor,” Dr. Griffin added.

Shaheen Lakhan, MD, PhD, a neurologist and researcher in Boston, agreed. “If you ever get up too quickly and feel woozy, that is your brain not getting enough blood flow and you are getting all the warning signs to correct that – or else! Similarly, with atrial fibrillation, the heart is contracting, but not effectively pumping blood to the brain,” he said.

“This line of research shows that correcting the abnormal heart rhythm by zapping the faulty circuit with a catheter is actually better for your brain health than just taking medications alone,” added Dr. Lakhan, who was not involved with the study.

The study had no commercial funding. Dr. Srichawla, Dr. Griffin, and Dr. Lakhan report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Last week, unbeknownst to most people, Dayton, Ohio, hosted the world championships of Winter Drumline. It’s a combination of percussion instruments, dance, and music, with a storyline. Think of it as a very fast-paced half-time show, with only percussion, in 6 minutes or less.

My daughter fell in love with it her second year of high school, and has participated in it through college. Her specialty is the pit – marimba, vibraphone, xylophone. This gives our house a cruise ship atmosphere when she comes home to practice on weekends.

Over the years my wife and I have gone to many of her shows and competitions, streamed others online, and always been amazed by the variety of costumes, choreography, music numbers, and overall themes different teams come up with. We’ve seen shows based on 1930s detective fiction, ocean life, westerns, science fiction, toxic waste, emotions, relationships, flamenco, pirate ships, and many others.

And, as always, I marvel at the human brain.

Only 2-3 pounds but still an amazing thing. The capacity for imagination is endless, and one of the things that got us where we are today. The ability to see things that don’t exist yet, and work out the details on how to get there. The pyramids, Petra, the Great Wall, flight, the steam engine, landing on the moon, the ISS. And, of course, Winter Drumline.

It’s a uniquely (as far as we know) human capacity. To look at a rock and envision what it might be carved into. To look at Jupiter and think of a way to get a probe there. To sit in an empty gym and imagine the floor covered with dozens of percussion instruments and their players, imagining what each will be playing and doing at a given moment.

It’s really a remarkable capacity when you think about it. I’m sure it originally began as a way to figure out where you might find shelter or food, or simply to outwit the other tribe. But it’s become so much more than that. Someone envisioned every movie you see, book you read, and the computer I’m writing this on.

In his 1968 novelization of “2001: A Space Odyssey” Arthur C. Clarke described the thoughts of the unknown civilization that had left the Monolith behind for us as “in all the galaxy they had found nothing more precious than Mind.”

I’d agree with that. Even after 30 years of learning about the 2-3 pounds of semi-solid tissue we all carry upstairs, and doing my best to treat its malfunctions, I’ve never ceased to be amazed by it.

I hope I always will be.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

Last week, unbeknownst to most people, Dayton, Ohio, hosted the world championships of Winter Drumline. It’s a combination of percussion instruments, dance, and music, with a storyline. Think of it as a very fast-paced half-time show, with only percussion, in 6 minutes or less.

My daughter fell in love with it her second year of high school, and has participated in it through college. Her specialty is the pit – marimba, vibraphone, xylophone. This gives our house a cruise ship atmosphere when she comes home to practice on weekends.

Over the years my wife and I have gone to many of her shows and competitions, streamed others online, and always been amazed by the variety of costumes, choreography, music numbers, and overall themes different teams come up with. We’ve seen shows based on 1930s detective fiction, ocean life, westerns, science fiction, toxic waste, emotions, relationships, flamenco, pirate ships, and many others.

And, as always, I marvel at the human brain.

Only 2-3 pounds but still an amazing thing. The capacity for imagination is endless, and one of the things that got us where we are today. The ability to see things that don’t exist yet, and work out the details on how to get there. The pyramids, Petra, the Great Wall, flight, the steam engine, landing on the moon, the ISS. And, of course, Winter Drumline.

It’s a uniquely (as far as we know) human capacity. To look at a rock and envision what it might be carved into. To look at Jupiter and think of a way to get a probe there. To sit in an empty gym and imagine the floor covered with dozens of percussion instruments and their players, imagining what each will be playing and doing at a given moment.

It’s really a remarkable capacity when you think about it. I’m sure it originally began as a way to figure out where you might find shelter or food, or simply to outwit the other tribe. But it’s become so much more than that. Someone envisioned every movie you see, book you read, and the computer I’m writing this on.

In his 1968 novelization of “2001: A Space Odyssey” Arthur C. Clarke described the thoughts of the unknown civilization that had left the Monolith behind for us as “in all the galaxy they had found nothing more precious than Mind.”

I’d agree with that. Even after 30 years of learning about the 2-3 pounds of semi-solid tissue we all carry upstairs, and doing my best to treat its malfunctions, I’ve never ceased to be amazed by it.

I hope I always will be.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

Last week, unbeknownst to most people, Dayton, Ohio, hosted the world championships of Winter Drumline. It’s a combination of percussion instruments, dance, and music, with a storyline. Think of it as a very fast-paced half-time show, with only percussion, in 6 minutes or less.

My daughter fell in love with it her second year of high school, and has participated in it through college. Her specialty is the pit – marimba, vibraphone, xylophone. This gives our house a cruise ship atmosphere when she comes home to practice on weekends.

Over the years my wife and I have gone to many of her shows and competitions, streamed others online, and always been amazed by the variety of costumes, choreography, music numbers, and overall themes different teams come up with. We’ve seen shows based on 1930s detective fiction, ocean life, westerns, science fiction, toxic waste, emotions, relationships, flamenco, pirate ships, and many others.

And, as always, I marvel at the human brain.

Only 2-3 pounds but still an amazing thing. The capacity for imagination is endless, and one of the things that got us where we are today. The ability to see things that don’t exist yet, and work out the details on how to get there. The pyramids, Petra, the Great Wall, flight, the steam engine, landing on the moon, the ISS. And, of course, Winter Drumline.

It’s a uniquely (as far as we know) human capacity. To look at a rock and envision what it might be carved into. To look at Jupiter and think of a way to get a probe there. To sit in an empty gym and imagine the floor covered with dozens of percussion instruments and their players, imagining what each will be playing and doing at a given moment.

It’s really a remarkable capacity when you think about it. I’m sure it originally began as a way to figure out where you might find shelter or food, or simply to outwit the other tribe. But it’s become so much more than that. Someone envisioned every movie you see, book you read, and the computer I’m writing this on.

In his 1968 novelization of “2001: A Space Odyssey” Arthur C. Clarke described the thoughts of the unknown civilization that had left the Monolith behind for us as “in all the galaxy they had found nothing more precious than Mind.”

I’d agree with that. Even after 30 years of learning about the 2-3 pounds of semi-solid tissue we all carry upstairs, and doing my best to treat its malfunctions, I’ve never ceased to be amazed by it.

I hope I always will be.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

Early menopause and delayed initiation of hormone therapy (HT) have been linked to an increase in Alzheimer’s disease (AD) pathology in women, a new imaging study shows.

Investigators found elevated levels of tau protein in the brains of women who initiated HT more than 5 years after menopause onset, while those who started the therapy earlier had normal levels.

Tau levels were also higher in women who started menopause before age 45, either naturally or following surgery, but only in those who already had high levels of beta-amyloid.

The findings were published online in JAMA Neurology.
 

Hotly debated

Previous research has suggested the timing of menopause and HT initiation may be associated with AD. However, the current research is the first to suggest tau deposition may explain that link.

“There have been a lot of conflicting findings around whether HT induces risk for Alzheimer’s disease dementia or not, and – at least in our hands – our observational evidence suggests that any risk is fairly limited to those rarer cases when women might delay their initiation of HT considerably,” senior investigator Rachel Buckley, PhD, assistant investigator in neurology at Massachusetts General Hospital and assistant professor of neurology at Harvard Medical School, Boston, told this news organization.

The link between HT, dementia, and cognitive decline has been hotly debated since the initial release of findings from the Women’s Health Initiative Memory Study, reported 20 years ago.

Since then, dozens of studies have yielded conflicting evidence about HT and AD risk, with some showing a protective effect and others showing the treatment may increase AD risk.

For this study, researchers analyzed data from 292 cognitively unimpaired participants (66.1% female) in the Wisconsin Registry for Alzheimer Prevention. About half of the women had received HT.

Women had higher levels of tau measured on PET imaging than age-matched males, even after adjustment for APOE status and other potential confounders.

Higher tau levels were found in those with an earlier age at menopause (P < .001) and HT use (P = .008) compared with male sex; later menopause onset; or HT nonuse – but only in patients who also had a higher beta-amyloid burden.

Late initiation of HT (> 5 years following age at menopause) was associated with higher tau compared with early initiation (P = .001), regardless of amyloid levels.
 

Surprising finding

Although researchers expected to find that surgical history (specifically oophorectomy) might have a greater impact on risk, that wasn’t the case.

“Given that bilateral oophorectomy involves the removal of both ovaries, and the immediate ceasing of estrogen production, I had expected this to be the primary driver of higher tau levels,” Dr. Buckley said. “But early age at menopause – regardless of whether the genesis was natural or surgical – seemed to have similar impacts.”

These findings are the latest from Dr. Buckley’s group that indicate that women tend to have higher levels of tau than men, regardless of preexisting amyloid burden in the brain.

“We see this in healthy older women, women with dementia, and even in postmortem cases,” Dr. Buckley said. “It really remains to be seen whether women tend to accumulate tau faster in the brain than men, or whether this is simply a one-shot phenomenon that we see in observational studies at the baseline.”

“One could really flip this finding on its head and suggest that women are truly resilient to the disease,” she continued. “That is, they can hold much more tau in their brain and remain well enough to be studied, unlike men.”

Among the study’s limitations is that the data were collected at a single time point and did not include information on subsequent Alzheimer’s diagnosis or cognitive decline.

“It is important to remember that the participants in this study were not as representative of the general population in the United States, so we cannot extrapolate our findings to women from a range of socioeconomic, racial and ethnic backgrounds or education levels,” she said.

The study’s observational design left researchers unable to demonstrate causation. What’s more, the findings don’t support the assertion that hormone therapy may protect against AD, Dr. Buckley added.

“I would more confidently say that evidence from our work, and that of many others, seems to suggest that HT initiated around the time of menopause may be benign – not providing benefit or risk, at least in the context of Alzheimer’s disease risk,” she said.

Another important takeaway from the study, Dr. Buckley said, is that not all women are at high risk for AD.

“Often the headlines might make you think that most women are destined to progress to dementia, but this simply is not the case,” Dr. Buckley said. “We are now starting to really drill down on what might elevate risk for AD in women and use this information to better inform clinical trials and doctors on how best to think about treating these higher-risk groups.”
 

New mechanism?

Commenting on the findings, Pauline Maki, PhD, professor of psychiatry, psychology and obstetrics & gynecology at the University of Illinois at Chicago, called the study “interesting.”

“It identifies a new mechanism in humans that could underlie a possible link between sex hormones and dementia,” Dr. Maki said.

However, Dr. Maki noted that the study wasn’t randomized and information about menopause onset was self-reported.

“We must remember that many of the hypotheses about hormone therapy and brain health that came from observational studies were not validated in randomized trials, including the hypothesis that hormone therapy prevents dementia,” she said.

The findings don’t resolve the debate over hormone therapy and AD risk and point to the need for randomized, prospective studies on the topic, Dr. Maki added. Still, she said, they underscore the gender disparity in AD risk.

“It’s a good reminder to clinicians that women have a higher lifetime risk of Alzheimer’s disease and should be advised on factors that might lower their risk,” she said.

The study was funded by the National Institutes of Health. Dr. Buckley reports no relevant financial conflicts. Dr. Maki serves on the advisory boards for Astellas, Bayer, Johnson & Johnson, consults for Pfizer and Mithra, and has equity in Estrigenix, Midi-Health, and Alloy.
 

A version of this article originally appeared on Medscape.com.

Early menopause and delayed initiation of hormone therapy (HT) have been linked to an increase in Alzheimer’s disease (AD) pathology in women, a new imaging study shows.

Investigators found elevated levels of tau protein in the brains of women who initiated HT more than 5 years after menopause onset, while those who started the therapy earlier had normal levels.

Tau levels were also higher in women who started menopause before age 45, either naturally or following surgery, but only in those who already had high levels of beta-amyloid.

The findings were published online in JAMA Neurology.
 

Hotly debated

Previous research has suggested the timing of menopause and HT initiation may be associated with AD. However, the current research is the first to suggest tau deposition may explain that link.

“There have been a lot of conflicting findings around whether HT induces risk for Alzheimer’s disease dementia or not, and – at least in our hands – our observational evidence suggests that any risk is fairly limited to those rarer cases when women might delay their initiation of HT considerably,” senior investigator Rachel Buckley, PhD, assistant investigator in neurology at Massachusetts General Hospital and assistant professor of neurology at Harvard Medical School, Boston, told this news organization.

The link between HT, dementia, and cognitive decline has been hotly debated since the initial release of findings from the Women’s Health Initiative Memory Study, reported 20 years ago.

Since then, dozens of studies have yielded conflicting evidence about HT and AD risk, with some showing a protective effect and others showing the treatment may increase AD risk.

For this study, researchers analyzed data from 292 cognitively unimpaired participants (66.1% female) in the Wisconsin Registry for Alzheimer Prevention. About half of the women had received HT.

Women had higher levels of tau measured on PET imaging than age-matched males, even after adjustment for APOE status and other potential confounders.

Higher tau levels were found in those with an earlier age at menopause (P < .001) and HT use (P = .008) compared with male sex; later menopause onset; or HT nonuse – but only in patients who also had a higher beta-amyloid burden.

Late initiation of HT (> 5 years following age at menopause) was associated with higher tau compared with early initiation (P = .001), regardless of amyloid levels.
 

Surprising finding

Although researchers expected to find that surgical history (specifically oophorectomy) might have a greater impact on risk, that wasn’t the case.

“Given that bilateral oophorectomy involves the removal of both ovaries, and the immediate ceasing of estrogen production, I had expected this to be the primary driver of higher tau levels,” Dr. Buckley said. “But early age at menopause – regardless of whether the genesis was natural or surgical – seemed to have similar impacts.”

These findings are the latest from Dr. Buckley’s group that indicate that women tend to have higher levels of tau than men, regardless of preexisting amyloid burden in the brain.

“We see this in healthy older women, women with dementia, and even in postmortem cases,” Dr. Buckley said. “It really remains to be seen whether women tend to accumulate tau faster in the brain than men, or whether this is simply a one-shot phenomenon that we see in observational studies at the baseline.”

“One could really flip this finding on its head and suggest that women are truly resilient to the disease,” she continued. “That is, they can hold much more tau in their brain and remain well enough to be studied, unlike men.”

Among the study’s limitations is that the data were collected at a single time point and did not include information on subsequent Alzheimer’s diagnosis or cognitive decline.

“It is important to remember that the participants in this study were not as representative of the general population in the United States, so we cannot extrapolate our findings to women from a range of socioeconomic, racial and ethnic backgrounds or education levels,” she said.

The study’s observational design left researchers unable to demonstrate causation. What’s more, the findings don’t support the assertion that hormone therapy may protect against AD, Dr. Buckley added.

“I would more confidently say that evidence from our work, and that of many others, seems to suggest that HT initiated around the time of menopause may be benign – not providing benefit or risk, at least in the context of Alzheimer’s disease risk,” she said.

Another important takeaway from the study, Dr. Buckley said, is that not all women are at high risk for AD.

“Often the headlines might make you think that most women are destined to progress to dementia, but this simply is not the case,” Dr. Buckley said. “We are now starting to really drill down on what might elevate risk for AD in women and use this information to better inform clinical trials and doctors on how best to think about treating these higher-risk groups.”
 

New mechanism?

Commenting on the findings, Pauline Maki, PhD, professor of psychiatry, psychology and obstetrics & gynecology at the University of Illinois at Chicago, called the study “interesting.”

“It identifies a new mechanism in humans that could underlie a possible link between sex hormones and dementia,” Dr. Maki said.

However, Dr. Maki noted that the study wasn’t randomized and information about menopause onset was self-reported.

“We must remember that many of the hypotheses about hormone therapy and brain health that came from observational studies were not validated in randomized trials, including the hypothesis that hormone therapy prevents dementia,” she said.

The findings don’t resolve the debate over hormone therapy and AD risk and point to the need for randomized, prospective studies on the topic, Dr. Maki added. Still, she said, they underscore the gender disparity in AD risk.

“It’s a good reminder to clinicians that women have a higher lifetime risk of Alzheimer’s disease and should be advised on factors that might lower their risk,” she said.

The study was funded by the National Institutes of Health. Dr. Buckley reports no relevant financial conflicts. Dr. Maki serves on the advisory boards for Astellas, Bayer, Johnson & Johnson, consults for Pfizer and Mithra, and has equity in Estrigenix, Midi-Health, and Alloy.
 

A version of this article originally appeared on Medscape.com.

Early menopause and delayed initiation of hormone therapy (HT) have been linked to an increase in Alzheimer’s disease (AD) pathology in women, a new imaging study shows.

Investigators found elevated levels of tau protein in the brains of women who initiated HT more than 5 years after menopause onset, while those who started the therapy earlier had normal levels.

Tau levels were also higher in women who started menopause before age 45, either naturally or following surgery, but only in those who already had high levels of beta-amyloid.

The findings were published online in JAMA Neurology.
 

Hotly debated

Previous research has suggested the timing of menopause and HT initiation may be associated with AD. However, the current research is the first to suggest tau deposition may explain that link.

“There have been a lot of conflicting findings around whether HT induces risk for Alzheimer’s disease dementia or not, and – at least in our hands – our observational evidence suggests that any risk is fairly limited to those rarer cases when women might delay their initiation of HT considerably,” senior investigator Rachel Buckley, PhD, assistant investigator in neurology at Massachusetts General Hospital and assistant professor of neurology at Harvard Medical School, Boston, told this news organization.

The link between HT, dementia, and cognitive decline has been hotly debated since the initial release of findings from the Women’s Health Initiative Memory Study, reported 20 years ago.

Since then, dozens of studies have yielded conflicting evidence about HT and AD risk, with some showing a protective effect and others showing the treatment may increase AD risk.

For this study, researchers analyzed data from 292 cognitively unimpaired participants (66.1% female) in the Wisconsin Registry for Alzheimer Prevention. About half of the women had received HT.

Women had higher levels of tau measured on PET imaging than age-matched males, even after adjustment for APOE status and other potential confounders.

Higher tau levels were found in those with an earlier age at menopause (P < .001) and HT use (P = .008) compared with male sex; later menopause onset; or HT nonuse – but only in patients who also had a higher beta-amyloid burden.

Late initiation of HT (> 5 years following age at menopause) was associated with higher tau compared with early initiation (P = .001), regardless of amyloid levels.
 

Surprising finding

Although researchers expected to find that surgical history (specifically oophorectomy) might have a greater impact on risk, that wasn’t the case.

“Given that bilateral oophorectomy involves the removal of both ovaries, and the immediate ceasing of estrogen production, I had expected this to be the primary driver of higher tau levels,” Dr. Buckley said. “But early age at menopause – regardless of whether the genesis was natural or surgical – seemed to have similar impacts.”

These findings are the latest from Dr. Buckley’s group that indicate that women tend to have higher levels of tau than men, regardless of preexisting amyloid burden in the brain.

“We see this in healthy older women, women with dementia, and even in postmortem cases,” Dr. Buckley said. “It really remains to be seen whether women tend to accumulate tau faster in the brain than men, or whether this is simply a one-shot phenomenon that we see in observational studies at the baseline.”

“One could really flip this finding on its head and suggest that women are truly resilient to the disease,” she continued. “That is, they can hold much more tau in their brain and remain well enough to be studied, unlike men.”

Among the study’s limitations is that the data were collected at a single time point and did not include information on subsequent Alzheimer’s diagnosis or cognitive decline.

“It is important to remember that the participants in this study were not as representative of the general population in the United States, so we cannot extrapolate our findings to women from a range of socioeconomic, racial and ethnic backgrounds or education levels,” she said.

The study’s observational design left researchers unable to demonstrate causation. What’s more, the findings don’t support the assertion that hormone therapy may protect against AD, Dr. Buckley added.

“I would more confidently say that evidence from our work, and that of many others, seems to suggest that HT initiated around the time of menopause may be benign – not providing benefit or risk, at least in the context of Alzheimer’s disease risk,” she said.

Another important takeaway from the study, Dr. Buckley said, is that not all women are at high risk for AD.

“Often the headlines might make you think that most women are destined to progress to dementia, but this simply is not the case,” Dr. Buckley said. “We are now starting to really drill down on what might elevate risk for AD in women and use this information to better inform clinical trials and doctors on how best to think about treating these higher-risk groups.”
 

New mechanism?

Commenting on the findings, Pauline Maki, PhD, professor of psychiatry, psychology and obstetrics & gynecology at the University of Illinois at Chicago, called the study “interesting.”

“It identifies a new mechanism in humans that could underlie a possible link between sex hormones and dementia,” Dr. Maki said.

However, Dr. Maki noted that the study wasn’t randomized and information about menopause onset was self-reported.

“We must remember that many of the hypotheses about hormone therapy and brain health that came from observational studies were not validated in randomized trials, including the hypothesis that hormone therapy prevents dementia,” she said.

The findings don’t resolve the debate over hormone therapy and AD risk and point to the need for randomized, prospective studies on the topic, Dr. Maki added. Still, she said, they underscore the gender disparity in AD risk.

“It’s a good reminder to clinicians that women have a higher lifetime risk of Alzheimer’s disease and should be advised on factors that might lower their risk,” she said.

The study was funded by the National Institutes of Health. Dr. Buckley reports no relevant financial conflicts. Dr. Maki serves on the advisory boards for Astellas, Bayer, Johnson & Johnson, consults for Pfizer and Mithra, and has equity in Estrigenix, Midi-Health, and Alloy.
 

A version of this article originally appeared on Medscape.com.

Adopting a Mediterranean diet may improve cognition in patients who have multiple sclerosis (MS) due to a potential neuroprotective mechanism, according to findings of a study that was released early, ahead of presentation at the annual meting of the American Academy of Neurology.

“We were most surprised by the magnitude of the results,” said Ilana Katz Sand, MD, associate professor of neurology at the Corinne Goldsmith Dickinson Center for MS at Mount Sinai in New York. “We hypothesized a significant association between Mediterranean diet and cognition in MS, but we did not anticipate the 20% absolute difference, particularly because we rigorously controlled the demographic and health-related factors, like socioeconomic status, body mass index, and exercise habits.”

Corinne Goldsmith Dickinson Center for MS at Mount Sinai

The Mediterranean diet consists of predominately vegetables, fruits, legumes, fish, and healthy fats while minimizing the consumption of dairy products, meats, and saturated acids. Previous literature has drawn an association between diet and MS symptomology, notably with regard to the Mediterranean diet. These studies indicated a connection between thalamic volume in patients with early MS as well as objectively captured MS-related disability. In this study, researchers have continued their investigation by exploring how the Mediterranean diet affects cognition.

In this cross-sectional observational study, investigators evaluated 563 people with MS ranging in age from 18 to 65 years (n = 563; 71% women; aged 44.2 ± 11.3 years). To accomplish this task, researchers conducted a retrospective chart review capturing data from patients with MS who had undergone neurobehavioral screenings. Qualifying subjects completed the Mediterranean Diet Adherence Screener (MEDAS) to determine the extent to which they adhered to the Mediterranean diet. A 14-item questionnaire, MEDAS assess a person’s usual intake of healthful foods such as vegetables and olive oil, as well as minimization of unhealthy foods such as butter and red meat. They also completed an analogue of the CICMAS cognitive battery comprised of a composite of Symbol Digit Modalities Test, Hopkins Verbal Learning Test, Revised, and CANTAB Paired Associate Learning.

Researchers evaluated patient-reported outcomes adjusted based on demographics (i.e., age, sex, race, ethnicity, and socioeconomic status) and health-related factors. These elements included body mass index, exercise, sleep disturbance, hypertension, diabetes, hyperlipidemia, and smoking.

The study excluded patients who had another primary neurological condition in addition to MS (n = 24), serious psychiatric illness such as schizophrenia (n = 5) or clinical relapse within 6 weeks (n = 2), or missing data (n = 13).

Based on the diet scores, investigators stratified participants into four groups. Those with the scores ranging from 0 to 4 were classified into the lowest group, while scores of 9 or greater qualified participants for the high group.

Investigators observed a significant association between a higher Mediterranean diet score and condition in the population sampled. They found a mean z-score of –0.67 (0.95). In addition, a higher MEDAS proved an independent indicator of better cognition (B = 0.08 [95% confidence interval (CI), 0.05, 0.11], beta = 0.20, P < .001). In fact, a high MEDAS independently correlated to a 20% lower risk for cognitive impairment (odds ratio [OR] = .80 {95% CI, 0.73, 0.89}, P < .001). Ultimately, the study’s findings demonstrated MEDAS served as the strongest health-related indicator of z-score and cognitive impairment. Moreover, dietary modification based on effect suggested stronger associations between diet and cognition with progressive disease as opposed to relapsing disease, as noted by the relationship between the z-score and cognition.

“Further research is needed,” Dr. Katz Sand said. “But because the progressive phenotype reflects more prominent neurodegeneration, the greater observed effect size in those with progressive MS suggests a potential neuroprotective mechanism.”

This study was funded in part by an Irma T. Hirschl/Monique Weill-Caulier Research Award to Dr. Katz Sand. Dr. Katz Sand and coauthors also received funding from the National Multiple Sclerosis Society.

Adopting a Mediterranean diet may improve cognition in patients who have multiple sclerosis (MS) due to a potential neuroprotective mechanism, according to findings of a study that was released early, ahead of presentation at the annual meting of the American Academy of Neurology.

“We were most surprised by the magnitude of the results,” said Ilana Katz Sand, MD, associate professor of neurology at the Corinne Goldsmith Dickinson Center for MS at Mount Sinai in New York. “We hypothesized a significant association between Mediterranean diet and cognition in MS, but we did not anticipate the 20% absolute difference, particularly because we rigorously controlled the demographic and health-related factors, like socioeconomic status, body mass index, and exercise habits.”

Corinne Goldsmith Dickinson Center for MS at Mount Sinai

The Mediterranean diet consists of predominately vegetables, fruits, legumes, fish, and healthy fats while minimizing the consumption of dairy products, meats, and saturated acids. Previous literature has drawn an association between diet and MS symptomology, notably with regard to the Mediterranean diet. These studies indicated a connection between thalamic volume in patients with early MS as well as objectively captured MS-related disability. In this study, researchers have continued their investigation by exploring how the Mediterranean diet affects cognition.

In this cross-sectional observational study, investigators evaluated 563 people with MS ranging in age from 18 to 65 years (n = 563; 71% women; aged 44.2 ± 11.3 years). To accomplish this task, researchers conducted a retrospective chart review capturing data from patients with MS who had undergone neurobehavioral screenings. Qualifying subjects completed the Mediterranean Diet Adherence Screener (MEDAS) to determine the extent to which they adhered to the Mediterranean diet. A 14-item questionnaire, MEDAS assess a person’s usual intake of healthful foods such as vegetables and olive oil, as well as minimization of unhealthy foods such as butter and red meat. They also completed an analogue of the CICMAS cognitive battery comprised of a composite of Symbol Digit Modalities Test, Hopkins Verbal Learning Test, Revised, and CANTAB Paired Associate Learning.

Researchers evaluated patient-reported outcomes adjusted based on demographics (i.e., age, sex, race, ethnicity, and socioeconomic status) and health-related factors. These elements included body mass index, exercise, sleep disturbance, hypertension, diabetes, hyperlipidemia, and smoking.

The study excluded patients who had another primary neurological condition in addition to MS (n = 24), serious psychiatric illness such as schizophrenia (n = 5) or clinical relapse within 6 weeks (n = 2), or missing data (n = 13).

Based on the diet scores, investigators stratified participants into four groups. Those with the scores ranging from 0 to 4 were classified into the lowest group, while scores of 9 or greater qualified participants for the high group.

Investigators observed a significant association between a higher Mediterranean diet score and condition in the population sampled. They found a mean z-score of –0.67 (0.95). In addition, a higher MEDAS proved an independent indicator of better cognition (B = 0.08 [95% confidence interval (CI), 0.05, 0.11], beta = 0.20, P < .001). In fact, a high MEDAS independently correlated to a 20% lower risk for cognitive impairment (odds ratio [OR] = .80 {95% CI, 0.73, 0.89}, P < .001). Ultimately, the study’s findings demonstrated MEDAS served as the strongest health-related indicator of z-score and cognitive impairment. Moreover, dietary modification based on effect suggested stronger associations between diet and cognition with progressive disease as opposed to relapsing disease, as noted by the relationship between the z-score and cognition.

“Further research is needed,” Dr. Katz Sand said. “But because the progressive phenotype reflects more prominent neurodegeneration, the greater observed effect size in those with progressive MS suggests a potential neuroprotective mechanism.”

This study was funded in part by an Irma T. Hirschl/Monique Weill-Caulier Research Award to Dr. Katz Sand. Dr. Katz Sand and coauthors also received funding from the National Multiple Sclerosis Society.

Adopting a Mediterranean diet may improve cognition in patients who have multiple sclerosis (MS) due to a potential neuroprotective mechanism, according to findings of a study that was released early, ahead of presentation at the annual meting of the American Academy of Neurology.

“We were most surprised by the magnitude of the results,” said Ilana Katz Sand, MD, associate professor of neurology at the Corinne Goldsmith Dickinson Center for MS at Mount Sinai in New York. “We hypothesized a significant association between Mediterranean diet and cognition in MS, but we did not anticipate the 20% absolute difference, particularly because we rigorously controlled the demographic and health-related factors, like socioeconomic status, body mass index, and exercise habits.”

Corinne Goldsmith Dickinson Center for MS at Mount Sinai

The Mediterranean diet consists of predominately vegetables, fruits, legumes, fish, and healthy fats while minimizing the consumption of dairy products, meats, and saturated acids. Previous literature has drawn an association between diet and MS symptomology, notably with regard to the Mediterranean diet. These studies indicated a connection between thalamic volume in patients with early MS as well as objectively captured MS-related disability. In this study, researchers have continued their investigation by exploring how the Mediterranean diet affects cognition.

In this cross-sectional observational study, investigators evaluated 563 people with MS ranging in age from 18 to 65 years (n = 563; 71% women; aged 44.2 ± 11.3 years). To accomplish this task, researchers conducted a retrospective chart review capturing data from patients with MS who had undergone neurobehavioral screenings. Qualifying subjects completed the Mediterranean Diet Adherence Screener (MEDAS) to determine the extent to which they adhered to the Mediterranean diet. A 14-item questionnaire, MEDAS assess a person’s usual intake of healthful foods such as vegetables and olive oil, as well as minimization of unhealthy foods such as butter and red meat. They also completed an analogue of the CICMAS cognitive battery comprised of a composite of Symbol Digit Modalities Test, Hopkins Verbal Learning Test, Revised, and CANTAB Paired Associate Learning.

Researchers evaluated patient-reported outcomes adjusted based on demographics (i.e., age, sex, race, ethnicity, and socioeconomic status) and health-related factors. These elements included body mass index, exercise, sleep disturbance, hypertension, diabetes, hyperlipidemia, and smoking.

The study excluded patients who had another primary neurological condition in addition to MS (n = 24), serious psychiatric illness such as schizophrenia (n = 5) or clinical relapse within 6 weeks (n = 2), or missing data (n = 13).

Based on the diet scores, investigators stratified participants into four groups. Those with the scores ranging from 0 to 4 were classified into the lowest group, while scores of 9 or greater qualified participants for the high group.

Investigators observed a significant association between a higher Mediterranean diet score and condition in the population sampled. They found a mean z-score of –0.67 (0.95). In addition, a higher MEDAS proved an independent indicator of better cognition (B = 0.08 [95% confidence interval (CI), 0.05, 0.11], beta = 0.20, P < .001). In fact, a high MEDAS independently correlated to a 20% lower risk for cognitive impairment (odds ratio [OR] = .80 {95% CI, 0.73, 0.89}, P < .001). Ultimately, the study’s findings demonstrated MEDAS served as the strongest health-related indicator of z-score and cognitive impairment. Moreover, dietary modification based on effect suggested stronger associations between diet and cognition with progressive disease as opposed to relapsing disease, as noted by the relationship between the z-score and cognition.

“Further research is needed,” Dr. Katz Sand said. “But because the progressive phenotype reflects more prominent neurodegeneration, the greater observed effect size in those with progressive MS suggests a potential neuroprotective mechanism.”

This study was funded in part by an Irma T. Hirschl/Monique Weill-Caulier Research Award to Dr. Katz Sand. Dr. Katz Sand and coauthors also received funding from the National Multiple Sclerosis Society.

Obstructive sleep apnea (OSA) may be associated with early cognitive decline in middle-aged men, new research shows.

In a pilot study out of King’s College London, participants with severe OSA experienced worse executive functioning as well as social and emotional recognition versus healthy controls.

Major risk factors for OSA include obesity, high blood pressure, smoking, high cholesterol, and being middle-aged or older. Because some researchers have hypothesized that cognitive deficits could be driven by such comorbidities, the study investigators recruited middle-aged men with no medical comorbidities.

“Traditionally, we were more concerned with sleep apnea’s metabolic and cardiovascular comorbidities, and indeed, when cognitive deficits were demonstrated, most were attributed to them, and yet, our patients and their partners/families commonly tell us differently,” lead investigator Ivana Rosenzweig, MD, PhD, of King’s College London, who is also a consultant in sleep medicine and neuropsychiatry at Guy’s and St Thomas’ Hospital, London, said in an interview.

“Our findings provide a very important first step towards challenging the long-standing dogma that sleep apnea has little to do with the brain – apart from causing sleepiness – and that it is a predominantly nonneuro/psychiatric illness,” added Dr. Rosenzweig.

The findings were published online in Frontiers in Sleep.
 

Brain changes

The researchers wanted to understand how OSA may be linked to cognitive decline in the absence of cardiovascular and metabolic conditions.

To accomplish this, the investigators studied 27 men between the ages of 35 and 70 with a new diagnosis of mild to severe OSA without any comorbidities (16 with mild OSA and 11 with severe OSA). They also studied a control group of seven men matched for age, body mass index, and education level.

The team tested participants’ cognitive performance using the Cambridge Neuropsychological Test Automated Battery and found that the most significant deficits for the OSA group, compared with controls, were in areas of visual matching ability (P < .0001), short-term visual recognition memory, nonverbal patterns, executive functioning and attentional set-shifting (P < .001), psychomotor functioning, and social cognition and emotional recognition (P < .05).

On the latter two tests, impaired participants were less likely to accurately identify the emotion on computer-generated faces. Those with mild OSA performed better than those with severe OSA on these tasks, but rarely worse than controls.

Dr. Rosenzweig noted that the findings were one-of-a-kind because of the recruitment of patients with OSA who were otherwise healthy and nonobese, “something one rarely sees in the sleep clinic, where we commonly encounter patients with already developed comorbidities.

“In order to truly revolutionize the treatment for our patients, it is important to understand how much the accompanying comorbidities, such as systemic hypertension, obesity, diabetes, hyperlipidemia, and other various serious cardiovascular and metabolic diseases and how much the illness itself may shape the demonstrated cognitive deficits,” she said.

She also said that “it is widely agreed that medical problems in middle age may predispose to increased prevalence of dementia in later years.

Moreover, the very link between sleep apnea and Alzheimer’s, vascular and mixed dementia is increasingly demonstrated,” said Dr. Rosenzweig.

Although women typically have a lower prevalence of OSA than men, Dr. Rosenzweig said women were not included in the study “because we are too complex. As a lifelong feminist it pains me to say this, but to get any authoritative answer on our physiology, we need decent funding in place so that we can take into account all the intricacies of the changes of our sleep, physiology, and metabolism.

“While there is always lots of noise about how important it is to answer these questions, there are only very limited funds available for the sleep research,” she added.

Dr. Rosenzweig’s future research will focus on the potential link between OSA and neuroinflammation.

In a comment, Liza Ashbrook, MD, associate professor of neurology at the University of California, San Francisco, said the findings “add to the growing list of negative health consequences associated with sleep apnea.”

She said that, if the cognitive changes found in the study are, in fact, caused by OSA, it is unclear whether they are the beginning of long-term cognitive changes or a symptom of fragmented sleep that may be reversible.

Dr. Ashbrook said she would be interested in seeing research on understanding the effect of OSA treatment on the affected cognitive domains.

The study was funded by the Wellcome Trust. No relevant financial relationships were reported.

A version of this article originally appeared on Medscape.com.

Obstructive sleep apnea (OSA) may be associated with early cognitive decline in middle-aged men, new research shows.

In a pilot study out of King’s College London, participants with severe OSA experienced worse executive functioning as well as social and emotional recognition versus healthy controls.

Major risk factors for OSA include obesity, high blood pressure, smoking, high cholesterol, and being middle-aged or older. Because some researchers have hypothesized that cognitive deficits could be driven by such comorbidities, the study investigators recruited middle-aged men with no medical comorbidities.

“Traditionally, we were more concerned with sleep apnea’s metabolic and cardiovascular comorbidities, and indeed, when cognitive deficits were demonstrated, most were attributed to them, and yet, our patients and their partners/families commonly tell us differently,” lead investigator Ivana Rosenzweig, MD, PhD, of King’s College London, who is also a consultant in sleep medicine and neuropsychiatry at Guy’s and St Thomas’ Hospital, London, said in an interview.

“Our findings provide a very important first step towards challenging the long-standing dogma that sleep apnea has little to do with the brain – apart from causing sleepiness – and that it is a predominantly nonneuro/psychiatric illness,” added Dr. Rosenzweig.

The findings were published online in Frontiers in Sleep.
 

Brain changes

The researchers wanted to understand how OSA may be linked to cognitive decline in the absence of cardiovascular and metabolic conditions.

To accomplish this, the investigators studied 27 men between the ages of 35 and 70 with a new diagnosis of mild to severe OSA without any comorbidities (16 with mild OSA and 11 with severe OSA). They also studied a control group of seven men matched for age, body mass index, and education level.

The team tested participants’ cognitive performance using the Cambridge Neuropsychological Test Automated Battery and found that the most significant deficits for the OSA group, compared with controls, were in areas of visual matching ability (P < .0001), short-term visual recognition memory, nonverbal patterns, executive functioning and attentional set-shifting (P < .001), psychomotor functioning, and social cognition and emotional recognition (P < .05).

On the latter two tests, impaired participants were less likely to accurately identify the emotion on computer-generated faces. Those with mild OSA performed better than those with severe OSA on these tasks, but rarely worse than controls.

Dr. Rosenzweig noted that the findings were one-of-a-kind because of the recruitment of patients with OSA who were otherwise healthy and nonobese, “something one rarely sees in the sleep clinic, where we commonly encounter patients with already developed comorbidities.

“In order to truly revolutionize the treatment for our patients, it is important to understand how much the accompanying comorbidities, such as systemic hypertension, obesity, diabetes, hyperlipidemia, and other various serious cardiovascular and metabolic diseases and how much the illness itself may shape the demonstrated cognitive deficits,” she said.

She also said that “it is widely agreed that medical problems in middle age may predispose to increased prevalence of dementia in later years.

Moreover, the very link between sleep apnea and Alzheimer’s, vascular and mixed dementia is increasingly demonstrated,” said Dr. Rosenzweig.

Although women typically have a lower prevalence of OSA than men, Dr. Rosenzweig said women were not included in the study “because we are too complex. As a lifelong feminist it pains me to say this, but to get any authoritative answer on our physiology, we need decent funding in place so that we can take into account all the intricacies of the changes of our sleep, physiology, and metabolism.

“While there is always lots of noise about how important it is to answer these questions, there are only very limited funds available for the sleep research,” she added.

Dr. Rosenzweig’s future research will focus on the potential link between OSA and neuroinflammation.

In a comment, Liza Ashbrook, MD, associate professor of neurology at the University of California, San Francisco, said the findings “add to the growing list of negative health consequences associated with sleep apnea.”

She said that, if the cognitive changes found in the study are, in fact, caused by OSA, it is unclear whether they are the beginning of long-term cognitive changes or a symptom of fragmented sleep that may be reversible.

Dr. Ashbrook said she would be interested in seeing research on understanding the effect of OSA treatment on the affected cognitive domains.

The study was funded by the Wellcome Trust. No relevant financial relationships were reported.

A version of this article originally appeared on Medscape.com.

Obstructive sleep apnea (OSA) may be associated with early cognitive decline in middle-aged men, new research shows.

In a pilot study out of King’s College London, participants with severe OSA experienced worse executive functioning as well as social and emotional recognition versus healthy controls.

Major risk factors for OSA include obesity, high blood pressure, smoking, high cholesterol, and being middle-aged or older. Because some researchers have hypothesized that cognitive deficits could be driven by such comorbidities, the study investigators recruited middle-aged men with no medical comorbidities.

“Traditionally, we were more concerned with sleep apnea’s metabolic and cardiovascular comorbidities, and indeed, when cognitive deficits were demonstrated, most were attributed to them, and yet, our patients and their partners/families commonly tell us differently,” lead investigator Ivana Rosenzweig, MD, PhD, of King’s College London, who is also a consultant in sleep medicine and neuropsychiatry at Guy’s and St Thomas’ Hospital, London, said in an interview.

“Our findings provide a very important first step towards challenging the long-standing dogma that sleep apnea has little to do with the brain – apart from causing sleepiness – and that it is a predominantly nonneuro/psychiatric illness,” added Dr. Rosenzweig.

The findings were published online in Frontiers in Sleep.
 

Brain changes

The researchers wanted to understand how OSA may be linked to cognitive decline in the absence of cardiovascular and metabolic conditions.

To accomplish this, the investigators studied 27 men between the ages of 35 and 70 with a new diagnosis of mild to severe OSA without any comorbidities (16 with mild OSA and 11 with severe OSA). They also studied a control group of seven men matched for age, body mass index, and education level.

The team tested participants’ cognitive performance using the Cambridge Neuropsychological Test Automated Battery and found that the most significant deficits for the OSA group, compared with controls, were in areas of visual matching ability (P < .0001), short-term visual recognition memory, nonverbal patterns, executive functioning and attentional set-shifting (P < .001), psychomotor functioning, and social cognition and emotional recognition (P < .05).

On the latter two tests, impaired participants were less likely to accurately identify the emotion on computer-generated faces. Those with mild OSA performed better than those with severe OSA on these tasks, but rarely worse than controls.

Dr. Rosenzweig noted that the findings were one-of-a-kind because of the recruitment of patients with OSA who were otherwise healthy and nonobese, “something one rarely sees in the sleep clinic, where we commonly encounter patients with already developed comorbidities.

“In order to truly revolutionize the treatment for our patients, it is important to understand how much the accompanying comorbidities, such as systemic hypertension, obesity, diabetes, hyperlipidemia, and other various serious cardiovascular and metabolic diseases and how much the illness itself may shape the demonstrated cognitive deficits,” she said.

She also said that “it is widely agreed that medical problems in middle age may predispose to increased prevalence of dementia in later years.

Moreover, the very link between sleep apnea and Alzheimer’s, vascular and mixed dementia is increasingly demonstrated,” said Dr. Rosenzweig.

Although women typically have a lower prevalence of OSA than men, Dr. Rosenzweig said women were not included in the study “because we are too complex. As a lifelong feminist it pains me to say this, but to get any authoritative answer on our physiology, we need decent funding in place so that we can take into account all the intricacies of the changes of our sleep, physiology, and metabolism.

“While there is always lots of noise about how important it is to answer these questions, there are only very limited funds available for the sleep research,” she added.

Dr. Rosenzweig’s future research will focus on the potential link between OSA and neuroinflammation.

In a comment, Liza Ashbrook, MD, associate professor of neurology at the University of California, San Francisco, said the findings “add to the growing list of negative health consequences associated with sleep apnea.”

She said that, if the cognitive changes found in the study are, in fact, caused by OSA, it is unclear whether they are the beginning of long-term cognitive changes or a symptom of fragmented sleep that may be reversible.

Dr. Ashbrook said she would be interested in seeing research on understanding the effect of OSA treatment on the affected cognitive domains.

The study was funded by the Wellcome Trust. No relevant financial relationships were reported.

A version of this article originally appeared on Medscape.com.