Advancements in the field of mental health continue to emerge, making it challenging for clinicians to stay up to date with the latest findings. This article highlights recent developments in our understanding of mental health conditions and the therapies used to treat them.

WIDESPREAD PRESCRIBING OF STIMULANTS WITH OTHER CNS MEDS

Despite an incomplete understanding of the mechanism of action of central nervous system (CNS) stimulants such as amphetamine and methylphenidate, these therapies have been in use for several decades and are indicated for a number of diseases. In the United States, these drugs have been classified as Schedule II controlled substances, along with other medications, owing to the risk of addiction associated with their use.^[1]

A new study revealed that a large proportion of US adults who are prescribed Schedule II stimulants are simultaneously receiving other CNS agents including benzodiazepines, opioids, and antidepressants — a potentially dangerous practice.

Investigators analyzed prescription drug claims for over 9.1 million US adults over a 1-year period and found that 276,223 (3%) had used a Schedule II stimulant, such as methylphenidate and amphetamines, during that time. Of these 276,223 patients, 45% combined these agents with 1 or more additional CNS drugs and almost 25% were simultaneously using 2 or more additional CNS-active drugs. Close to half of the stimulant users were taking an antidepressant, while close to one third filled prescriptions for anxiolytic/sedative/hypnotic meditations, and one fifth received opioid prescriptions.

The widespread, often off-label use of these stimulants, in combination therapy with antidepressants, anxiolytics, opioids, and other psychoactive drugs, "reveals new patterns of utilization beyond the approved use of stimulants as monotherapy for attention deficit hyperactivity disorder (ADHD), but because there are so few studies of these kinds of combination therapy, both the advantages and additional risks [of this type of prescribing] remain unknown," study investigator Thomas J. Moore, AB, faculty associate in epidemiology, Johns Hopkins Bloomberg School of Public Health and Johns Hopkins Medicine, Baltimore, Maryland, told Medscape Medical News.

The study was published online April 24 in BMJ Open.^[1]

"Dangerous" Substances

Amphetamines and methylphenidate are CNS stimulants that have been in use for almost a century. Like opioids and barbiturates, they're considered "dangerous" and classified as Schedule II Controlled Substances because of their high potential for abuse.^[2] Over many years, these stimulants have been used for multiple purposes, including nasal congestion, narcolepsy, appetite suppression, binge eating, depression, senile behavior, lethargy, and ADHD, the researchers note.

Observational studies suggest medical use of these agents has been increasing in the United States. The investigators conducted previous research that revealed a 79% increase from 2013 to 2018 in the number of adults who self-report their use. The current study, said Moore, explores how these stimulants are being used.

For the study, data were extracted from the Market-Scan 2019 and 2020 Commercial Claims and Encounters Databases, focusing on 9.1 million adults aged 19-64 years who were continuously enrolled in an included commercial benefit plan from October 1, 2019 to December 31, 2020. The primary outcome consisted of an outpatient prescription claim, service date, and days' supply for the CNS-active drugs.

The researchers defined "combination-2" therapy as 60 or more days of combination treatment with a Schedule II stimulant and at least 1 additional CNS-active drug. "Combination-3" therapy was defined as the addition of at least 2 additional CNS-active drugs. The researchers used service date and days' supply to examine the number of stimulant and other CNS-active drugs for each of the days of 2020. CNS-active drug classes included antidepressants, anxiolytics/sedatives/hypnotics, antipsychotics, opioids, anticonvulsants, and other CNS-active drugs.

Prescribing Cascade

Of the total number of adults enrolled, 3% (n = 276,223) were taking Schedule II stimulants during 2020, with a median of 8 (interquartile range 4-11) prescriptions. These drugs provided 227 (IQR 110-322) treatment days of exposure. Among those taking stimulants 45.5% combined the use of at least 1 additional CNS-active drug for a median of 213 (IQR 126-301) treatment days; and 24.3% used at least 2 additional CNS-active drugs for a median of 182 (IQR 108-276) days.

Table: Other CNS-Active Drugs by Drug Class Among Those Exposed to Schedule II Stimulants in 2020.

"Clinicians should beware of the prescribing cascade. Sometimes it begins with an antidepressant that causes too much sedation, so a stimulant gets added, which leads to insomnia, so alprazolam gets added to the mix," Moore said. He cautioned that this "leaves a patient with multiple drugs, all with discontinuation effects of different kinds and clashing effects."

These new findings, the investigators note, "add new public health concerns to those raised by our previous study...this more-detailed profile reveals several new patterns." Most patients become "long-term users" once treatment has started, with 75% continuing for a 1-year period. "This underscores the possible risks of non-medical use and dependence that have warranted the classification of these drugs as having high potential for psychological or physical dependence and their prominent appearance in toxicology drug rankings of fatal overdose cases," they write.

They note that the data "do not indicate which intervention may have come first — a stimulant added to compensate for excess sedation from the benzodiazepine, or the alprazolam added to calm excessive CNS stimulation and/or insomnia from the stimulants or other drugs."

Several limitations cited by the authors include the fact that, although the population encompassed 9.1 million people, it "may not represent all commercially insured adults" and it doesn't include people who aren't covered by commercial insurance. Moreover, the MarketScan dataset included up to 4 diagnosis codes for each outpatient and emergency department encounter; therefore, it was not possible to directly link the diagnoses to specific prescription drug claims, and thus the diagnoses were not evaluated.

"Since many providers will not accept a drug claim for a Schedule II stimulant without an on-label diagnosis of ADHD," the authors suspect that "large numbers of this diagnosis were present."

Complex Prescribing Regimens

Commenting for Medscape Medical News, Mark Olfson, MD, MPH, professor of psychiatry, medicine, and law and professor of epidemiology, Columbia University Irving Medical Center, New York City, said the report "highlights the pharmacological complexity of adults who are treated with stimulants."

Olfson, who is a research psychiatrist at the New York State Psychiatric Institute and was not involved with the study, observed there is "evidence to support stimulants as an adjunctive therapy for treatment-resistant unipolar depression in older adults." However, he added, "this indication is unlikely to fully explain the high proportion of non-elderly, stimulant-treated adults who also receive antidepressants." These new findings "call for research to increase our understanding of the clinical contexts that motivate these complex prescribing regimens as well as their effectiveness and safety," said Olfson.

ALZHEIMER'S RISK TIED TO INCREASED EPILEPSY RISK, AND VICE VERSA

Alzheimer’s disease (AD) is the most common form of dementia and poses a significant public health problem.^[3] Approximately 55 million people around the globe are living with dementia and AD comprises 60% to 70% of these cases.^[4] Furthermore, epilepsy is a commonly occurring nervous system disorder in older adults and patients with mild cognitive dysfunction have an increased risk for seizures.^[5] While some observational studies have suggested an association between AD and epilepsy, causality has not been clearly defined.^[6]

Results of a newly published, large genome-wide association study (GWAS) showed that a genetic predisposition for AD was associated with an increased risk of epilepsy, and vice versa.^[6] The study was published online May 24 in Neurology.

Vicious Cycle

"Accumulating evidence indicates a close association between AD and epilepsies" with preclinical studies suggesting a "vicious cycle" between them, the investigators note. Amyloid-beta has demonstrated epileptogenic potential, even in early stages of the amyloid cascade. On the other hand, epileptiform activity and chronic hyperexcitability may promote amyloid plaque deposits and tau hyperphosphorylation.

Human studies have pointed to a bidirectional association of epilepsy with AD. Given this close relationship, the investigators note that it is "essential to verify a true causal association, as such an association would indicate a potentially modifiable cause or previous underrecognized consequence of AD."

The researchers chose Mendelian randomization (MR) methodology because it "minimizes several inherent limitations of conventional observation studies, including unobserved confounding and reverse causality." The current study utilized 2-sample MR analyses, testing the hypotheses that AD drives epilepsy and that epilepsy drives AD. The researchers also studied the association between genetically predicted cerebrospinal fluid (CSF) markers of AD (amyloid-beta 42 and pTau) and epilepsy.

"Novel Evidence"

The investigators drew on GWAS summary statistics for epilepsy and subtypes from the International League Against Consortium on Complex Epilepsies (n = 15,212 cases and 29,677 controls). Phenotype categories included genetic generalized epilepsy, focal epilepsy (focal sclerosis, lesion other than HS, lesion-negative, and not otherwise specified), and unclassified epilepsy.

They also drew on data from an AD GWAS meta-analysis, which included patients with AD as well as proxy cases — ie, people with a family history of AD (n = 111,325 cases and proxies and 667,663 controls). To replicate positive findings, they used an earlier GWAS dataset that only enrolled late-onset AD cases. Genetic predictors of CSF AD markers were obtained from the European Alzheimer and Dementia Biobank (n = 13,116 European ancestry individuals).

Genetic predisposition to AD was associated with a higher risk of focal hippocampal sclerosis (HS) (odds ratio, 1.013; 95% CI: 1.004, 1.022; P = .004) — a finding replicated in sensitivity analyses. AD was also associated with an elevated risk of generalized epilepsy (OR, 1.053; 95% CI: 1.003, 1.105; P = .038), with sensitivity analyses yielding similar estimates in magnitude and direction.

The forward analysis (the effect of epilepsy on AD) showed a significant effect of focal HS on AD (OR, 3.994; 95% CI: 1.172 , 13.613; P = .027). But when the researchers attempted to replicate this finding using the other datasets, the estimated effect was not significant and, in fact, went in the opposite direction (P = .252).

Genetically predicted lower CSF amyloid-beta 42 was associated with a higher risk of generalized epilepsy (β = .090; 95% CI: 0.022, ~ 0.158; P = .010), with similar estimates found in sensitivity analyses. There was no significant effect of epilepsy on CSF biomarkers.

A limitation of the study is that participants were of European ancestry, so the results may not be generalizable to other populations.

The authors conclude that they have provided "novel evidence that AD was causally linked to generalized epilepsy and focal epilepsy with hippocampal sclerosis."

Confusing Nomenclature

Commenting for Medscape Medical News, Percy Griffin, PhD, Alzheimer's Association director of science engagement, called it "intriguing work, suggestive of possible treatment and prevention strategies that may be worth pursuing." However, it "does not have immediate clinical implications until it is replicated and confirmed in additional, more representative study populations," said Griffin, who was not involved with the study. He noted that current trials are investigating anti-seizure medications as possible treatments for AD.

Also commenting for Medscape Medical News, Jacqueline French, MD, professor of neurology, NYU Comprehensive Epilepsy Center, New York City, expressed concerns about the study. "In the 'discussion' section, the authors say that generalized epilepsy 'has been observed in 15% to 40% of patients with Alzheimer's at various disease stages,' but this is incorrect," said French, chief medical and innovation office for the Epilepsy Foundation of America, who was not involved with the study.

She explained that there is a difference between "generalized seizures" — ie, tonic-clonic seizures, which have been renamed "focal-to-bilateral" or "tonic-clonic bilateral" — vs "generalized epilepsy," which is idiopathic and rarely presents late in life, such as when a person might develop AD. "Most seizures that occur in people with Alzheimer's are focal, not generalized, and they don't have 'generalized epilepsy,' " she explained.

She agrees that there is a potential bidirectional link between AD and focal HS, "which makes more sense." However, French said the study's take-home message for patients with epilepsy is not that they will likely go on to develop AD. On the other hand, people with AD "have brains that are more hyperexcitable, which is a risk factor for seizures, and there is some evidence suggesting people with AD are at higher risk for focal epilepsy, but it's unlikely to come from a genetic predisposition," she said.

EMOTIONAL BLUNTING OF ANTIDEPRESSANTS UNDERAPPRECIATED

Serotonin reuptake inhibitors (SSRIs) are a commonly prescribed class of antidepressants. They are typically used as first-line treatment for depression and other mental health conditions because of their safety and efficacy profiles. SSRIs that are approved for use in the United States include fluoxetine, sertraline, fluvoxamine, paroxetine, citalopram, escitalopram, and vilazodone.^[7]

Emotional blunting can be described as feeling emotionally flat and incapable of finding pleasure. The patient may feel less sadness, guilt, or hopelessness but that may come at the cost of feeling less joy, surprise, and happiness. New research shows that patients taking antidepressant medication, especially SSRIs, often report emotional blunting even as their depression eases.^[8] Some people with SSRI-induced blunting even report caring less about important relationships.

It is an issue that needs greater attention, study investigator Mujeeb Shad, MD, with Valley Health Services and University of Nevada Las Vegas, told Medscape Medical News. "Patients may come to the clinic and report feeling emotionally and cognitively flat and not be taken seriously by their provider, but they are genuinely reporting something that is happening to them and decreasing their quality of life," Shad explained.

The study was presented at the American Psychiatric Association (APA) 2023 Annual Meeting.

Something 'Missing'

Shad said that the genesis for the study came from a resident who noticed that many patients receiving SSRIs reported feeling better and not as bothered by the depression, yet, at the same time, they felt something was "missing. Their families would say, 'You're better but you're not the same person.'"

To investigate further, the researchers did a "scoping review" of 25 original studies that assessed antidepressant-related emotional blunting. Until now, there hasn't been a systematic review of this issue, Shad said. Ten of the studies looked at the role of SSRIs in emotional blunting, whereas the other 16 looked at serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and second-generation antipsychotic medications.

The results of the review show that emotional blunting is a significant patient-reported concern. It often presents as a subjective complaint of changed personality, feeling a lesser intensity of overall emotions, and the manifestation of not being oneself often attributed to antidepressant use, the researchers found. Emotional blunting was more commonly associated with SSRIs than with the other medications in the studies.

Common clinical strategies to manage antidepressant-induced emotional blunting reported in the literature include dose reduction or switching to a different antidepressant class; however, the literature did not make did not make the distinction between emotional blunting as a primary symptom of depression or an adverse effect of antidepressants.

Shad told Medscape Medical News that there is a need to develop valid and reliable measures to assess emotional blunting related to antidepressants. He noted that optimal patient care should include pre- and posttreatment assessment of emotional blunting. One useful tool is the Oxford Questionnaire on the Emotional Side-Effects of Antidepressants.

Can't Get to the Top

Jacob Cross, MD, who was not involved in the study, said that he has seen the impact of antidepressant-related emotional blunting first-hand. "I've had multiple patients report emotional blunting on antidepressant therapy," Cross, with the Department of Psychiatry, Rush University, Chicago, told Medscape Medical News.

"These patients feel like their emotions are not as high and not as low; so they experience directional improvement, but they're still not feeling like they can get that top peak emotion. It's kind of similar to anhedonia. There just feeling like a little cut off, like they're climbing a cliff and just can't get to that top," Cross said. For a patient with emotional blunting, Cross said he might "switch to an antidepressant that's more stimulating like an SNRI from an SSRI. You could also lower the dose and see if that helps, but I usually change the drug class."

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