Advances in mental health care are continuously emerging, challenging all members of the interprofessional team to remain aware of updates in the field and their impact on clinical practice. This article highlights recent developments in our understanding of mental health conditions, and strategies to prevent and treat these disorders.

ERRATIC SLEEP, LACK OF ACTIVITY TIED TO WORSENING SCHIZOPHRENIA SYMPTOMS

Schizophrenia spectrum disorders (SSDs) are associated with debilitating symptoms that are classified as positive (eg, delusions and hallucinations) or negative (eg, apathy and paucity of speech).^[1,2] Individuals affected by SSDs have an increased risk of premature mortality, comorbidities including cardiovascular diseases and diabetes, and face significant social and economic burdens.^[3] New research shows that erratic sleep patterns, dysregulated transitions between sleep and wake cycles, and excessive sleep during the day are linked to a worsening of schizophrenia symptoms.^[1]

The findings also showed that people with SSDs who lived in residential facilities experienced rigid routines, which correlated with a higher degree of negative symptoms.

The rigid routines were problematic for the patients living in residential settings, lead investigator Fabio Ferrarelli, MD, PhD, told Medscape Medical News. Ferrarelli is an associate professor of psychiatry at the University of Pittsburgh School of Medicine. "Engaging in different activities at different times in activities associated with motivation and social interaction — this helps to ameliorate difficult-to-treat negative symptoms," he said.

The findings were published online April 14 in Molecular Psychiatry.^[1]

Need to Increase Activity Levels

While there is no shortage of research on sleep disturbances among people with schizophrenia, research focusing specifically on rest-activity rhythm (RAR) disturbances and their relationships to symptoms of schizophrenia has been limited by small sample sizes or the lack of a control group, the investigators note.

To address this research gap, the investigators recruited 230 patients with SSD from participating residential facilities and communities throughout Italy. The participants included 108 healthy control participants, 54 community-dwelling patients with SSD who were receiving outpatient services, and 68 patients with SSD who were living in residential facilities. All participants wore an actigraph for 7 consecutive days so that investigators could monitor sleep-wake patterns.

Compared with healthy control participants, both SSD groups had more total sleep time and spent more time resting or being passive (P < .001). In contrast, healthy control participants were much more active. Part of the explanation for this may be that most of the control participants had jobs or attended school. In addition, the investigators note that many medications used to treat SSD can be highly sedating, causing some patients to sleep up to 15 hours per day.

Among residential participants with SSD, there was a higher level of inter-daily stability and higher daily RAR fragmentation than occurred among healthy control participants or community-dwelling patients with SSD (P < .001). There was also a higher level of negative symptoms among residential participants with SSD than among the community-dwelling group with SSD.

When taken together, Ferrarelli and his team interpreted the findings to mean that inter-daily stability could reflect premature aging or neurodegenerative processes in patients with more severe forms of schizophrenia.

Another explanation could be that the rigid routine of the residential facility was making negative symptoms worse, Ferrarelli said. It is important to add variety into the mix — getting people to engage in different activities at different times of day would likely help residential SSD patients overcome negative symptoms of the disorder. Although participants were recruited in Italy, Ferrarelli said he believes the findings are generalizable.

Bidirectional Relationship?

Commenting on the findings for Medscape Medical News, Matcheri Keshavan, MD, professor of psychiatry at Harvard Medical School in Boston, Massachusetts, said the findings are consistent with "well-known clinical observations that SSD patients tend to spend more time in bed and have more dysregulated sleep.

"Negative symptoms are also common, especially in residential patients. However, it is difficult to determine causality, as we do not know whether excessive sleepiness and decreased physical activity cause negative symptoms, or vice versa, or whether this is a bidirectional relationship," Keshavan said.

He emphasized that physical exercise is known to increase sleep quality for people with mental illness and may also improve negative symptoms.^[4,5] "A useful approach in clinical practice is to increase activity levels, especially physical activities like walking and gardening."

Keshavan said he would like to see future research that focuses on whether an intervention such as aerobic exercise would improve sleep quality as well as negative symptoms. He also said that future research should ideally examine the characteristics of sleep alterations in schizophrenia.

"For example, while sleep duration is increased in schizophrenia, studies suggest that time spent in deep sleep is reduced; sleep spindles, which are important for consolidating memory during sleep, are also reduced. Correcting these deficits may improve negative symptoms and cognitive deficits," he added.

The study was funded by the Italian Ministry of Health and the National Institute of Mental Health. There were no conflicts of interest.

PHYSICAL EXERCISE TIED TO A REDUCTION IN SUICIDE ATTEMPTS

Each year, around 700,000 people across the globe die because of suicide, and the number of suicide attempts is even greater. Suicide predominantly affects low- and middle-income countries, with 77% of cases occurring in these nations.^[6] However, it is also the tenth most common cause of death in the United States. ^[7] Novel research suggests that physical exercise is associated with a reduction in suicide attempts.^[8]

A meta-analysis of 17 randomized controlled trials (RCTs), which included more than 1000 participants with mental or physical illnesses, showed there was a significant reduction in suicide attempts in participants randomly assigned to receive exercise interventions, compared with inactive controls. However, there were no differences between the exercise and the control groups in suicidal ideation or mortality.

On the other hand, there was also no significant different in dropout rates between those randomly assigned to exercise vs inactive controls, suggesting that people with mental or physical impairments are able to adhere to exercise regimens.

"A common misconception is that patients, particularly those suffering from mental of physical illness, are not willing or motivated enough to participate in an exercise [regimen], and this has led to primary care providers underprescribing exercise to those with mental or physical illness," lead author Nicholas Fabiano, MD, a resident in the Department of Psychiatry at the University of Ottawa, Canada, told Medscape Medical News. As a result of the study findings, "we recommend that providers do not have apprehension about prescribing exercise to patients with physical or mental illness. Exercise may be an effective way to reduce suicidal behaviors" in these patients, he said.

The study was published online March 4 in the Journal of Affective Disorders.^[8]

Physical, Mental Health Strongly Linked

Existing literature has "demonstrated a protective effect of physical activity on suicidal ideation in the general population," but to date here have been no systematic reviews or meta-analyses investigating its impact on suicide-related outcomes in patients with physical or mental illness, the authors write.

"Those with mental or physical illness are at increased risk of suicide, compared to the general population," Fabiano commented. "We often split up 'mental health' and 'physical health' in medicine; however, I believe that the 2 are on a continuum and a holistic term, such as 'health,' should be used instead," he added.

He noted that mental and physical health are "inexorably intertwined" and those with physical illness are more prone to developing mental illness, whereas those with mental illness are more likely to suffer from a variety of other medical conditions. "Therefore, when treating those with mental illness, it is also imperative that we bolster one's physical health through easily accessible activities such as exercise," he said.

The goal of the study was to determine whether individuals with "any mental, physical, clinical, or subclinical condition" might benefit from exercise, particularly in relation to suicide-related outcomes. They searched multiple databases from inception to June 2022 to identify RCTs investigating exercise and suicidal ideation in participants with physical or mental conditions.^[8]

Of 673 studies, 17 met the inclusion criteria (total of 1021 participants). Participants' mean age was 42.7 years, 82% were female, and 54% were randomly assigned to an exercise intervention. Most studies (82%) focused on clinical vs subclinical outcomes. Depression was the most commonly included condition (59%). Aerobic exercise (53%) was the most common form of exercise used in the active study groups. This was followed by mind-body exercise and strength training (53%, 17.6%, and 17.6%, respectively). The mean follow-up time was 10 weeks.

Reduced Impulsivity

The researchers found a difference in post-intervention suicidal ideation when they compared exercise participants to all control and inactive control participants (standardized mean difference, –1.09; 95% CI: –3.08, 0.90; P = .20, k = 5). However, the difference was not statistically significant.^[8] Similarly, there was no significant difference (P = .60) in suicidal ideation incidence for subgroup analyses that stratified data among participants with depression, sickle cell disease, and suicidality.

All-cause discontinuation also did not significantly differ between participants who were randomly assigned to exercise interventions vs all controls or inactive controls (odds ratio [OR], 0.85; 95% CI: 0.38, 1.94; P = .86, k = 12 and OR, 0.81; 95% CI: 0.25, 2.68; P = .70). All-cause discontinuation also did not differ between participants randomized to exercise vs active controls (OR, 0.94; 95% CI: 0.38, 2.32; P = .79, k = 3).

Likewise, there were nonsignificant differences between participants who underwent aerobic exercise and strength training (P = .20). However, there were some nonsignificant differences when comparing participants with depression and stress who received the exercise intervention vs controls (P = .46).

There was a significant reduction in suicide attempts in individuals who participated in exercise interventions vs inactive controls (OR, 0.23; 95% CI: 0.09, 0.67; P = .04, k = 2). On the other hand, there was no significant difference in mortality (P = .70).

Most of the studies (82%) were "at high risk of bias," the authors note. In addition, the analysis was limited because the included studies were "few, underpowered, and heterogeneous."

Fabiano hypothesized that the lack of effect on suicidal ideation or mortality is "likely due to the limited sample size." As additional RCTs are conducted, Fabiano expects to see decreases in both suicidal ideation and suicide attempts." The findings may "be explained by the ideation-to-action framework, which suggests that the development of suicidal ideation and the progression to suicide attempts are distinct processes with different influential factors," he said. Increased levels of exercise have been "shown to reduce emotional impulsivity and, as it has been shown that most suicide attempts are characterized by impulsivity and low lethality, we hypothesize that regular exercise serves as a protective factor against suicide attempts," he said.

Not Useful?

Commenting for Medscape Medical News, Fabien Legrand, PhD, a lecturer in clinical psychology, University of Reims Champagne-Ardenne in Reims, France, said that the impact of physical activity is of "particular interest" to him because it is closely linked to his research activity, where he has "been exploring the antidepressant effects of exercise for more than 15 years."

A small pilot study conducted by Legrand and colleagues found rigorous physical activity to be helpful in reducing hopelessness in psychiatric patients, compared with controls. "This result is of particular relevance for suicidal patients since it has long been documented that hopelessness is one of the main triggers of suicide ideation and suicide attempts," he said.

Initially, Legrand "warmly welcomed" the current review and meta-analysis on the exercise and suicide. However, he felt that the paper fell short in accomplishing its intended goal. "After a thorough reading of the paper, I don't think that the information provided can be used in any way," he stated.

"The paper's title — 'Effects of Physical Exercise on Suicidal Ideation and Behavior' — does not do justice to its content, since 9 of the included 17 RCTs did not measure changes in suicidal ideation and/or suicidal behavior following participation in an exercise program," noted Legrand, who was not involved with authorship or the current analysis.

The study was funded by the University of Ottawa, Department of Psychiatry. Fabiano declares no relevant financial relationships. The other authors' disclosures are listed in the original article. Legrand declares no relevant financial relationships.

Batya Swift Yasgur, MA, LSW is a freelance writer with a counseling practice in Teaneck, NJ. She is a regular contributor to numerous medical publications, including Medscape and WebMD, and is the author of several consumer-oriented health books as well as Behind the Burqa: Our Lives in Afghanistan and How We Escaped to Freedom (the memoir of 2 brave Afghan sisters who told her their story).

ANTI-AMYLOIDS LINKED TO ACCELERATED BRAIN ATROPHY

Alzheimer’s disease (AD) is a progressive, neurodegenerative disorder that impacts cognitive function, particularly memory.^[9] The amyloid-beta (Aβ) pathway is thought to play a key role in the pathophysiology of AD,^[9] and anti-Aβ drugs have been developed and used in clinical practice to help treat patients.^[9,10] However, a comprehensive meta-analysis of magnetic resonance imaging (MRI) data from clinical trials suggests that these therapies have the potential to compromise long-term brain health by accelerating brain atrophy.^[10]

Depending on the anti-Aβ drug class, these agents can accelerate loss of whole brain and hippocampal volume and increase ventricular volume. This has been shown for some of the beta-secretase inhibitors and with several of the anti-amyloid monoclonal antibodies, researchers note.

"These data warrant concern, but we can't make any firm conclusions yet. It is possible that the finding is not detrimental, but the usual interpretation of this finding is that volume changes are a surrogate for disease progression," study investigator Scott Ayton, PhD, The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Australia, told Medscape Medical News. "These data should be factored into the decisions by clinicians when they consider prescribing anti-amyloid therapies. Like any side effect, clinicians should inform patients regarding the risk of brain atrophy. Patients should be actively monitored for this side effect," Ayton said.

The study was published online March 27 in Neurology.^[10]

Earlier Progression From MCI to AD?

Ayton and colleagues evaluated brain volume changes in 31 clinical trials of anti-Aβ drugs that demonstrated a favorable change in at least one biomarker of pathological Aβ and included detailed MRI data sufficient to assess the volumetric changes in at least one brain region.^[10]

A meta-analysis on the highest dose in each trial on the hippocampus, ventricles, and whole brain showed drug-induced acceleration of volume changes that varied by anti-Aβ drug class. Secretase inhibitors accelerated atrophy in the hippocampus (mean difference –37.1 μL; –19.6% relative to change in placebo) and whole brain (mean difference –3.3 mL; –21.8% relative to change in placebo), but not ventricles.

Conversely, monoclonal antibodies caused accelerated ventricular enlargement (mean difference +1.3 mL; +23.8% relative to change in placebo), which was driven by the subset of monoclonal antibodies that induce amyloid-related imaging abnormalities (ARIA) (+2.1 mL; +38.7% relative to change in placebo). There was a "striking correlation between ventricular volume and ARIA frequency," the investigators report.

The effect of ARIA-inducing monoclonal antibodies on whole brain volume varied, with accelerated whole brain volume loss caused by donanemab (mean difference –4.6 mL; +23% relative to change in placebo) and lecanemab (–5.2 mL; +36.4% relative to change in placebo). This was not observed with aducanumab and bapineuzumab. Monoclonal antibodies did not cause accelerated volume loss to the hippocampus regardless of whether they caused ARIA.

The researchers also modeled the effect of anti-Aβ drugs on brain volume changes. In this analysis, participants with mild cognitive impairment (MCI) treated with anti-Aβ drugs were projected to have a "material regression" toward brain volumes typical of AD roughly 8 months earlier than untreated peers.

The data, they note, "permit robust conclusions regarding the effect of anti-Aβ drug classes on different brain structures, but the lack of individual patient data (which has yet to be released) limits the interpretations of our findings. Questions like which brain regions are impacted by anti-Aβ drugs and whether the volume changes are related to ARIA, plaque loss, cognitive/noncognitive outcomes, or clinical factors such as age, sex, and APOE ε4 genotype can and should be addressed with available data," said Ayton.

Ayton and colleagues call on data safety monitoring boards (DSMBs) for current clinical trials of anti-Aβ drugs to review volumetric data to determine if patient safety is at risk, particularly in patients who develop ARIA. In addition, they note ethics boards that approve trials for anti-Aβ drugs "should request that volume changes be actively monitored. Long-term follow-up of brain volumes should be factored into the trial designs to determine if brain atrophy is progressive, particularly in patients who develop ARIA."

Finally, they add that drug companies that have conducted trials of anti-Aβ drugs should interrogate prior data on brain volume, report the findings, and release the data for researchers to investigate. "I have been banging on about this for years," said Ayton. "Unfortunately, my raising of this issue has not led to any response. The data are not available, and the basic questions haven't been asked (publicly)."

Commendable Research

In an accompanying editorial,^[11] Frederik Barkhof, MD, PhD, with Amsterdam University Medical Centers, Netherlands, and David Knopman, MD, with Mayo Clinic Alzheimer's Disease Research Center, Rochester, Minnesota, write that the investigators should be "commended" for their analysis. 

"The reality in 2023 is that the relevance of brain volume reductions in this therapeutic context remains uncertain," they write.

"Longer periods of observation will be needed to know whether the brain volume losses continue at an accelerated rate or if they attenuate or disappear. Ultimately, it's the clinical outcomes that matter, regardless of the MRI changes," Barkhof and Knopman conclude.

The research was supported by funds from the Australian National Health & Medical Research Council. Ayton has reported being a consultant for Eisai in the past 3 years. Barkhof has reported serving on the DSMB for Prothena and the A45-AHEAD studies; being a steering committee member for Merck, Bayer, and Biogen; and being a consultant for IXICO, Roche, Celltrion, Rewind Therapeutics, and Combinostics. Knopman has reported serving on the DSMD for the Dominantly Inherited Alzheimer Network Treatment Unit study; serving on a DSMB for a tau therapeutic for Biogen (until 2021); being an investigator for clinical trials sponsored by Biogen, Lilly Pharmaceuticals, and the University of Southern California. He has reported serving as a consultant for Roche, Samus Therapeutics, Magellan Health, BioVie, and Alzeca Biosciences; and attending an Eisai advisory board meeting for lecanemab in 2022.

This transcript has been edited for style and clarity.

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