The unintended negative consequences of the coronavirus disease 2019 (COVID-19) pandemic continues to be a problem. Reduced social interaction and closure of public places, along with increased home confinement, has led to a sharp decrease in physical activity, a steady increase in food intake, and a 

 Stress has similarly impacted sleep, unhealthy eating, and even increased consumption of alcohol.

Public health and economic crises have been associated with serious, long-lasting negative impact on individual and population-based mental health outcomes. Indeed, a recent meta-analysis found higher rates of 

, depression, posttraumatic stress disorder, psychological distress, and stress during the COVID-19 pandemic.

 To further complicate matters, individuals are less likely to seek non-emergent health care, including care for mental disorders, during the pandemic.

Related health consequences of obesity such as hypertension and diabetes mellitus are a major source of morbidity.

 Stress, fatigue, physical inactivity, and a sedentary lifestyle can advance obesity and, subsequently contribute to a number of mental health disorders.

 Depression and obesity share a bidirectional relationship, where the presence of one disease increases the risk for developing the other (

 Increased carbohydrate consumption, a risk factor for obesity, is common in patients with depression. The presence of obesity often has a chronic course of illness and can result in poor treatment response in depression.

 are predominantly treated with antidepressants as a first-line treatment option, with 79% of primary care physicians prescribing antidepressants to these patients.

 Recent studies have shown that antidepressant medications can contribute to weight gain through various mechanisms, including increased food consumption and abnormal metabolic processes.

 Reductions in depressive symptoms and antidepressant usage may coincide with weight loss (as seen with bariatric surgery patients), and this underscores the importance of monitoring the increasing rates of obesity.

For the last 2 decades, depressive disorders have consistently ranked amongst the top 5 illnesses for years of life lived with a disability.

 Cognitive deficits is a core symptom of depression, and it often persist between affective episodes and beyond the remission of mood symptoms.

 Executive functioning, attention, memory, and learning can be affected.

 Obesity also contributes to impairments in cognition; individuals with obesity exhibit significantly impaired cognitive functioning and structural changes in brain regions associated with executive functioning.

 Moreover, in individuals with obesity, cognitive impairments 

 lower weight loss success, poor treatment adherence, and decreased physical functioning.

Individuals with a longer duration of illness and a higher frequency of depressive episodes are more likely to experience cognitive impairments. Persistent cognitive impairment contributes to consequences in occupational and social domains.

 In particular, evidence from adults with mood disorders implicates cognitive impairment as a mediator of workplace function and attendance, as well as patient-reported outcomes (eg, quality of life).

 Approximately 15% of patients with major depressive disorder attribute their unemployment to cognitive symptoms. Unfortunately, few treatments, including psychotropic medications, have proven effective in improving cognitive function in adults with mood disorders, especially in cases of treatment resistance.

Patients with comorbid depression and obesity often demonstrate higher levels of baseline inflammation, which is characterized by a higher level of inflammatory cytokines (a type of signaling molecule that promotes inflammation). Likewise, obesity involves a pro-inflammatory state. Conversely, findings have shown improved cognition is linked to a reduction in inflammation.

 Indeed, in a meta-analysis evaluating inflammation and treatment response, researchers found increased levels of inflammatory cytokines in patients with depression. In cases that successfully responded to treatment, the levels of inflammatory cytokines were decreased.

There are several proposed mechanisms that may mediate the relationship between chronic stress, inflammation, and mood disorders. Stressful experiences have been shown to increase production of cortisol. Glucocorticoids increase activities of the sympathetic system, such as heart rate and blood pressure, to reduce the stress response. However, if this system is dysregulated, chronic stress and cortisol production can lead to the desensitization of the glucocorticoid receptors. It can be conjectured that the dysregulation of the inflammatory pathway is also worsened by the presence of insulin resistance and increase in adipocytes. The bidirectional relationship between the 2 illnesses and the co-occurrence of an inflammatory state underscores the involvement of inflammation in the pathophysiology of depression and obesity.

Evidence suggests that physical activity aids in alleviating mild to moderate symptoms of depression in patients and may promote clinically significant antidepressant effects. For more severe cases of depression, 

 in conjunction with other treatments (ie, pharmacological).

 Exercise may also help improve cognition in individuals with depression. In a study investigating the dose-dependent effects of 

 on cognition in patients with depression, high-intensity exercise was associated with improvements in executive function and working memory tasks. Meanwhile, other cognitive domains, such as attention, visual memory, and spatial planning, improved regardless of dose.

 Therefore, it is importan that adequate social and physical activities are integrated into treatment plans to promote well-being.

is a researcher at the Canadian Rapid Treatment Center of Excellence and the Institute of Medical Science at the University of Toronto. 

is a professor of psychiatry and pharmacology at the University of Toronto, and Head of the Mood Disorders Psychopharmacology Unit for the University Health Network, Toronto, Canada.

Effect of obesity and body mass index on coronavirus disease 2019 severity: A systematic review and meta‐analysis

2 .Xiong J, Lipsitz O, Nasri F, et al. Impact of COVID-19 pandemic on mental health in the general population: A systematic review.

3. Alosco ML, Spitznagel MB, Strain G, et al. Improved serum leptin and ghrelin following bariatric surgery predict better postoperative cognitive function.

4. Sarris J, O’Neil A, Coulson, et al. Lifestyle medicine for depression.

5. Luppino FS, de Wit LM, Bouvy PF, et al. Overweight, obesity, and depression: a systematic review and meta-analysis of longitudinal studies.

Collaborative care for depression in primary care: how psychiatry could “troubleshoot” current treatments and practices.

7. Gill H, Gill B, El-Halabi S, et al. Antidepressant Medications and Weight Change: A Narrative Review. (Silver Spring)

8. Collaborators G 2016 ORF, GBD 2016 Occupational Risk Factors Collaborators. Global and regional burden of disease and injury in 2016 arising from occupational exposures: a systematic analysis for the Global Burden of Disease Study 2016.

9. McIntyre RS, Lee Y. Cognition in major depressive disorder: a “Systemically Important Functional Index” (SIFI).

10. Motter JN, Pimontel MA, Rindskopf D, Devanand DP, Doraiswamy PM, Sneed JR. Computerized cognitive training and functional recovery in major depressive disorder: A meta-analysis.

11. Spitznagel MB, Garcia S, Miller LA, et al. Cognitive function predicts weight loss after bariatric surgery.

12. Rasmussen LJH, Caspi A, Ambler A, et al. 

Association of Neurocognitive and Physical Function With Gait Speed in Midlife

13. Baune BT, Air T. Clinical, Functional, and Biological Correlates of Cognitive Dimensions in Major Depressive Disorder – Rationale, Design, and Characteristics of the Cognitive Function and Mood Study (CoFaM-Study).

14. McIntyre RS, Lee Y, Mansur RB. Treating to target in major depressive disorder: response to remission to functional recovery.

15. Strawbridge R, Arnone D, Danese A, Papadopoulos A, Herane Vives A, Cleare AJ. Inflammation and clinical response to treatment in depression: A meta-analysis. 

16. Schuch FB, Vancampfort D, Richards J, et al. 

Exercise as a treatment for depression: A meta-analysis adjusting for publication bias

17. Greer TL, Grannemann BD, Chansard M, et al. Dose-dependent changes in cognitive function with exercise augmentation for major depression : results from the TREAD study. 

Articles

Evidence suggests that physical activity aids in alleviating mild to moderate symptoms of depression in patients and may promote clinically significant antidepressant effects.

A Recipe for Homemade Obesity: The Association Between Depression, Obesity, and Cognitive Deficits

As psychiatrists, we are constantly challenged by complex patients with a wide variety of clinical presentations. In fact, 2 patients with the same condition are never the same. Yet for all this diversity, there may be some common features. I propose that cognition is paramount in this respect.

 is a word that we use frequently, perhaps without pondering all that it entails. It is an important human attribute that has played a crucial part in our evolution. Yet the concept is so broad as to span many fields, from philosophy to psychology and the neurosciences. At the end of the day, we can all agree that cognition is essential for human fuctioning and flourishing.

Cognition involves many processes, both conscious and 

s. Different aspects include introspection, memory, learning, reasoning, perception, attention, problem solving, and the use of language. In some ways, this sounds so abstract that it is difficult to make practical sense of it. This is why I often reflect on my interactions with patients and what they have taught me.

On any given day, I see patients who are asymptomatic for their condition, yet they are certainly not enjoying a robust quality of life. For instance, one gentleman is without a doubt brilliant. He reads constantly and voraciously, and he can engage in a detailed discussion of various topics. After deciding that he wanted to read scripture in the original language, he learned several languages.

This patient is in remission from bipolar disorder. His scores are extremely low to nonexistent on the Patient Health Questionnaire (PHQ) 9, General Anxiety Disorder (GAD) 7, and Young Mania Rating Scale. Yet, he lacks significant organizational skills and has great difficulty in prioritizing tasks. This manifests in an extremely cluttered house, which is in shambles since his last manic episode approximately 2 years prior. Furthermore, this patient is obese and has increased inflammatory markers.

Another patient, a mechanical engineer who has been through extensive schooling and is given to preciseness, was seen by a neurologist who focuses on neurodegenerative disorders. His quantitative magnetic resonance imaging (MRI) showed no degeneration in his hippocampus. In addition, 

 showed no evidence of any memory disorder. He presented complaining of “adult-onset/attention deficit disorder.” Yet, on further exam, we realized his cognitive difficulties were due to depression.

Earlier I saw a woman who was morbidly obese. She very much wanted bariatric surgery and knee surgery for the immense pain. Her other physicians were in agreement with this plan. In the processes of her workup, she saw a sheet of labels with her name—the ones that are commonly used to identify information on documents or containers with biological specimens. The patient incorrectly deduced that each sticker was meant for a different test tube of blood. She thought the staff was going to draw at least 12 tubes; she began to think that she was going to be admitted against her will. It became clear that this patient was delusional; she was drawing incorrect cognitive conclusions that were negatively affecting her progress.

In addressing cognition, it is important to remember that psychotherapy, in addition to medications, can be an effective tool. Studies have demonstrated physical changes in the brain that occur as a result of effective psychotherapy. The work of 

, for instance, elucidated the synaptic changes related to memory and learning. (This won him, along with 2 others, the Nobel Prize for medicine in 2000.)

It is hard to overstate the importance of cognition in our day-to-day lives, especially as it relates to our work as psychiatrists. It is my hope that you will enjoy this 

 on cognition and that it serves as an appetizer to awaken a deeper hunger and curiosity.

is the medical director, Division of Neuropsychiatry, at Dent Neurologic Institute, and the medical director, Addiction Services, at Brylin Hospital in Buffalo, NY. The author(s) report no conflicts of interest concerning the subject matter of this article. ❒

In psychiatry, 2 patients with the same condition are never the same.

Diverse Patients, Common Ground

For more information, see the video series at 

https://www.psychiatrictimes.com/case-based-psych-perspectives/treating-schizophrenia-in-the-era-of-covid-19

There are many barriers to the successful treatment of schizophrenia, shared Bryce Reynolds, MD. In addition to patients’ lack of insight about their disease, schizophrenia is associated with cognitive deficits, social isolation, and cultural stigmas. Patients also face lack of motivation, transportation difficulties, and financial issues. These barriers are particularly relevant when addressing treatment adherence, especially with oral medications, and it can be difficult to truly assess adherence to oral medications.“We can’t absolutely guarantee that the person is consistently taking their PO [oral] medication,” stressed Reynolds. In his experience, there are generally 4 underlying reasons when symptoms worsen in a patient who previously achieved effective symptom management. He explained, “One is a decrease in adherence—the others are a medical comorbidity, a substance abuse comorbidity, or a major stressor that may cause an increase in their symptoms, even if they’re on their medication.”

The use of a long-acting injectable antipsychotic (LAI) medication can help overcome the clinical challenges associated with treating schizophrenia, especially adherence. There is an important pharmacokinetic benefit of LAIs, he explained. If a patient on a LAI does not receive an injection on schedule, there is “some additional time where [the LAIs are] still at a therapeutic serum level.” Compared with oral antipsychotic medications, LAI medications offer an extended time to relapse or decompensation. Reynolds emphasized that a longer time to relapse provides patients with benefits such as, “the ability to work and sustain housing and socialization and employment and going to school [for longer periods of time].” Since adherence is a known component for patients who use an LAI, Reynolds noted their contribution to an episode of decompensation is clearer.

Hannah Phillips-Hall, MSN, PMHNP-BC, who joined Reynolds in the discussion, added she is able to identify the possible cause more readily when a patient who is on an LAI decompensates.

Guideline-Recommended Schizophrenia Management with LAIs

Guidelines for the treatment of patients with schizophrenia from the American Psychiatric Association (APA) were updated in 2020 and emphasize a patient-centered treatment plan that includes evidence-based nonpharmacological and pharmacological treatments. Reynold’s summarized the APA guidelines and recommendations updates for LAI treatment in 3 applications: if it is preferred by the patient; if the patient has a history of poor adherence to oral therapy; and/or the patient’s future adherence to oral medications is questionable or uncertain in the judgment of the provider.

Both Reynolds and Phillips-Hall noted that offering a LAI upfront would be advantageous for several populations in which adherence to oral therapy is uncertain, such as for those with a history of substance use disorder, and those who are homeless or lack transportation to a pharmacy. Reynolds explained, “There is a benefit that the APA has recognized [in] getting them on LAIs, even before you see adherence issues. In fact, in my practice, the first day that I see them is the day that I offer a LAI to them.”

Phillips-Hall added, “Having those [APA] guidelines further validates [the use of LAIs] for the purpose of reimbursement and approval.”

There is an opportunity to implement early treatment with LAIs, which the faculty noted may improve treatment success. For instance, a patient who is diagnosed in their late teens or early 20s may go through 4 cycles of PO medications before they are offered an LAI at age 38. “[In essence], we wait until [their disease] gets really bad before we bring out the tool that perhaps could have kept them from getting bad in the first place,” Reynolds said. Phillips-Hall agreed, noting that offering a LAI upfront is a better way to set up newly diagnosed patients for success versus waiting for them to experience treatment failure with several oral medications.

Patient-Focused Care and Shared Decision Making

Reynolds emphasized the importance of correcting patient misconceptions and empowering them with choices about their treatment using motivational interviewing. Through his own use of this interview technique, Reynolds has identified 4 common patient-reported barriers to LAI treatment selection: 1) feeling that they have no control over the medication schedule, as they would with a pill or tablet; 2) a negative experience with a first-generation oil-based product (eg, knots at site of administration); 3) association of injections with being restrained in the emergency department (ED) during acute episodes of agitation; and 4) fear of injection-associated pain. Understanding these concerns allows clinicians to better address them. Reynolds finds it helpful to “normalize” his patients’ feelings by expressing his understanding of their fears. He then discusses LAIs in the context of the patient’s personal life goals, and points out how their current oral regimen is not helping them achieve their personal goals.

“Some studies show that 60% of people will take LAIs if presented [to them] well. That’s an extremely high number,” Reynolds said. As part of this presentation, the faculty suggested offering a short-term trial of an LAI, as it may help patients feel a greater sense of control over their treatment. “When patients are involved in a collaborative way to make an informed decision, many of them [try the LAI],” Reynolds explained. Since LAIs are available in several administration schedule options, Phillips-Hall noted it empowers the patient to choose how frequently they receive their medicine. Reynolds added that only having to receive medication 4 times a year has been very appealing to some of his patients.

Sesame oil-based first-generation antipsychotic LAIs are associated with more injection site pain, which can be also be addressed. Reynolds and Phillips-Hall indicated that injection-associated pain and discomfort can often be minimized by using second-generation antipsychotic LAIs, or by using an LAI with a small injection volume or decreased administration frequency.

Opportunities to Address Adherence During the COVID-19 Pandemic

As a result of the coronavirus disease (COVID-19) pandemic, patients with schizophrenia have experienced a reduction in their access to care as well as medication access challenges. Therefore, they experienced difficulty maintaining medication adherence. Given reduced office hours in many health care settings, it may be difficult for patients who are decompensating to receive medication adjustments from their provider or pick up their prescription from the pharmacy. For patients on oral medications, Phillips-Hall tries to make sure she prescribes a 90-day supply if their insurance will accommodate such. However, she also noted that the increased availability of, and insurance coverage for, telehealth services as a result of COVID-19 has been a silver lining in patient care.

Although there are additional safety risks associated with in-office visits for administration of LAIs during COVID-19, the faculty noted that routine safety measures can help mitigate the risk of exposure. Improvements in adherence with LAIs may help prevent hospitalizations, which in turn may prevent inadvertent exposure to the COVID-19 virus. “With the COVID risk, you want to limit that risk of hospitalization and going to the ED [due to] the exposure they may have in the ED,” said Reynolds.

Phillips-Hall added that COVID-19 has helped patients and families be more open-minded toward use of LAIs.

Reynolds added, “during the pandemic, LAI administration has been suspended in some areas where it’s identified as an elective procedure. The APA is encouraging hospitals and facilities to continue the use of LAIs for patients at high risk and [to] consider it a necessary procedure.”

When offering advice to community psychiatrists treating patients with schizophrenia, Reynolds said, “All it takes is a little compassion and using the right tools, and I would say LAIs are absolutely one of those right tools.” ❒

This article provides a summary of key points discussed in a Case-Based Psych Perspectives Series, shared by Bryce Reynolds, MD, and Hannah Phillips-Hall, MSN, PMHNP-BC. 

Case-Based Psych Perspectives: Treating Schizophrenia in the Era of COVID-19 

Schizophrenia is associated with an increased prevalence of alcohol use disorder (AUD),

 which is also associated with relapse and 

 Adherence with (limited) treatment options for this patient population are suboptimal. Furthermore, patients with comorbid AUD are often excluded from pharmacologic trials in schizophrenia. Therefore, this represents an understudied and difficult-to-treat patient population.

Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), funded by the 

, was a large, long comparative series of trials of antipsychotics for the treatment of schizophrenia.

 As effectiveness trials, CATIE did not exclude patients with substance use comorbidity.

“Ms Norman” is in her 40s and has a longstanding history of 

 and severe AUD. She binges on alcohol episodically, with several months’ sobriety between periods of heavy drinking. Typically, within several weeks of alcohol cessation, she will experience an exacerbation of psychosis requiring inpatient psychiatric hospitalization. She previously lived independently and was able to have part-time employment. Following a recent illness exacerbation, she experienced a period of homelessness for several months, during which she continued to drink alcohol and dropped out of outpatient psychiatric treatment.

 reported on a post hoc analysis of the course of illness in patients with schizophrenia and AUD from the CATIE study. They assessed time to first and recurrent exacerbation, and risks of first and current hospitalization within the 5 years before study entry for patients with this comorbidity, compared with patients with schizophrenia only. They also compared treatment outcomes with olanzapine versus other antipsychotics in these 2 groups. The authors hypothesized that patients with schizophrenia plus AUD would have worse outcomes than patients with schizophrenia alone and, within each group, the advantages of olanzapine for exacerbations and hospitalizations would be retained.

Data for the study were obtained from the publicly available, limited-access CATIE study dataset from the NIMH. Briefly, CATIE was an 18-month, double-blind, randomized trial of perphenazine, olanzapine, quetiapine, risperidone, and ziprasidone in 1493 patients with schizophrenia. The primary end point was time to all-cause discontinuation.

Patients were categorized into schizophrenia and AUD and schizophrenia-only groups (based on DSM-IV criteria). The authors excluded 155 patients with nonalcohol substance-use disorders, except for marijuana use, which was permitted. Exacerbation was defined as hospitalization for psychopathology; more than a 25% or 15-point increase in baseline 

 (PANSS) total score, or significant worsening of key PANSS items; clinically significant aggression or suicidal/homicidal ideation; use of rescue medication; emergency department visit; discontinuation due to lack of efficacy; or arrest or incarceration. Times to first and recurrent exacerbations and hospitalizations were compared, including the reasons leading to exacerbations. In the schizophrenia and AUD group, exacerbations and hospitalizations were compared between patients taking olanzapine and those taking other antipsychotics. There were 303 (23%) participants in the 

 and AUD group and 1035 (77%) in the schizophrenia-only group. Patients with schizophrenia and AUD were significantly younger, had a lower body mass index, were more likely to be male, and had a greater number of hospitalizations in the year prior to study entry than those with schizophrenia only. There was little difference in the prevalence of marijuana use between the 2 groups.

Both the time to first exacerbation (median, 5.4 versus 6.4 months; HR, 1.20) and time to first hospitalization (HR, 1.63) were significantly shorter in the schizophrenia and AUD group than the schizophrenia-only group (

). A similar finding was observed for recurrent hospitalizations (HR, 1.60), although there was only a trend for between-group differences in recurrent exacerbations. More than half (61%) of patients with schizophrenia and AUD had an exacerbation, compared with 52% in the schizophrenia-only group, and the patients with schizophrenia and AUD were more likely to have an exacerbation resulting in hospitalization for psychopathology, due to aggression or suicidal/homicidal ideation, or arrest or incarceration.

Overall, perphenazine, quetiapine, risperidone, and ziprasidone were all associated with a significantly shorter time to first exacerbation compared with olanzapine (HRs, 1.81-2.80). A similar pattern of findings was observed for time to first hospitalization.

The authors concluded that patients with schizophrenia plus AUD had a poorer course of illness, with higher risk of disease progression, compared with patients with only schizophrenia. The investigators also found that olanzapine may be associated with longer time to first and recurrent exacerbations compared with other treatments in patients with schizophrenia and AUD comorbidity.

“Mr Greggs” is in his 30s with a history of chronic schizophrenia and severe AUD, as well as cannabis use disorder. He is currently serving a 1-year probation for a driving-while-impaired citation. He is adherent with monthly administration of a long-acting injectable antipsychotic but continues to drink alcohol and smoke marijuana regularly. He lives at home with his parents and is chronically unemployed. He has not had a psychiatric hospitalization in many years but remains precontemplative regarding the need for treatment for substance use disorder.

Strengths of the present study included the large number of subjects and the real-world design of the CATIE trial. Potential limitations included the post hoc nature of the analysis as well as the lack of generalizability of findings to patients with schizophrenia and other (nonalcohol) substance use disorders. Future trials are needed to identify effective treatment for this patient population.

Patients with schizophrenia with alcohol use disorder comorbidity versus those without have a worse course of illness, and olanzapine may be associated with a longer time to exacerbations versus other nonclozapine antipsychotics.

is professor, Department of Psychiatry and Health Behavior, Augusta University, Augusta, GA. He is the schizophrenia section chief for 

. The author reports that he receives research support from Augusta University, the National Institute of Mental Health, the Brain & Behavior Research Foundation, and the Stanley Medical Research Institute.

1. Hartz SM, Pato CN, Medeiros H, et al; Genomic Psychiatry Cohort Consortium. Comorbidity of severe psychotic disorders with measures of substance use. 

2. Bradizza CM, Stasiewicz PR, Dermen KH. 

Behavioral interventions for individuals dually-diagnosed with a severe mental illness and a substance use disorder

3. Jones RM, Lichtenstein P, Grann M, Långström N, Fazel S. Alcohol use disorders in schizophrenia: a national cohort study of 12,653 patients. 

4. Lieberman JA, Stroup TS, McEvoy JP, et al; Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. 

5. Pathak S, Jiang Y, DiPetrillo L, Todtenkopf MS, Liu Y, Correll CU. 

Course of psychosis in schizophrenia with alcohol use disorder: a post hoc analysis of the Clinical Antipsychotic Trials of Intervention Effectiveness in Schizophrenia phase 1 study

Navigating the treatment options for comorbid schizophrenia and alcohol use

Schizophrenia and AUD

Six-Month LAI for Schizophrenia in the Works

Janssen Pharmaceutical Companies of Johnson & Johnson announced their supplemental New Drug Application (sNDA) submission for paliperidone palmitate 6-month (PP6M). If approved, PP6M will be the first and only long-acting injectable (LAI) medication for schizophrenia with a biannual dosing regimen.

Janssen’s submission to the US Food and Drug Administration (FDA) is based on the Route 6 Study, a randomized, double-blind, Phase III global study with 702 adult participants from 20 countries who were diagnosed with schizophrenia. Data showed PP6M’s efficacy in comparison to paliperidone palmitate 3-month (PP3M) in 2 analysis sets, intent-to-treat and per-protocol, for relapse times at the end of the 12-month period. The observed safety profile was consistent with previous studies.

“Antipsychotic medication plays an important role in schizophrenia symptom control; however, nonadherence to prescribed medicines has been recognized as a problem worldwide,” Mathai Mammen, MD, PhD, Global Head of Janssen Research & Development, LLC, told press. “Addressing this challenging aspect of treatment has been the catalyst for our research and development of long-acting injectable medications for people living with schizophrenia.”

PP6M is intended to be used only after patients are stabilized using another short-acting paliperidone palmitate. The overall goal is to administer fewer injections to patients.

The Neurobiological Mechanism for Hallucinations and Delusions

A new study from researchers at Columbia University Vagelos College of Physicians and Surgeons may have discovered a link between hallucinations/delusions and psychosis, thereby explaining their clinical presentation.

Researchers collected data from 127 patients diagnosed with schizophrenia from online databases. Kenneth Wengler, PhD, a postdoctoral research fellow at Columbia, and colleagues discovered that neural timelines in the lower levels of the hierarchal model of psychosis tended to be longer for patients with severe hallucinations, whereas neural timescales in the higher levels of the hierarchal model of psychosis tended to be longer for patients with severe delusions. This discovery is the first piece of direct evidence of a potential neurobiological mechanism for hallucinations and delusions.

Using functional magnetic resonance imaging, researchers measured intrinsic neural timescales in the brain to determine whether the mechanisms of hallucinations and delusions function within the hierarchical model. By examining specific regions of the brain, the research team could evaluate whether neural timelines reflected how long information took to integrate.

“Our findings open the door for the development of treatments to target specific symptoms of psychosis depending on an individual subject’s symptom profile, in line with the current push for individualized medicine,” Guillermo Horga, MD, PhD, Florence Irving Associate Professor of Psychiatry, said in a press statement.

1. Janssen Submits Paliperidone Palmitate 6-Month (PP6M) Supplemental New Drug Application to US FDA for Treatment of Schizophrenia in Adults. Johnson & Johnson. News release. November 2, 2020. Accessed November 12, 2020. 

http://johnsonandjohnson.gcs-web.com/news-releases/news-release-details/janssen-submits-paliperidone-palmitate-6-month-pp6m-supplemental

2. Wengler K, Goldberg AT, Chahine G, Horga G. Distinct hierarchical alterations of intrinsic neural timescales account for different manifestations of psychosis. eLife. October 27, 2020. Accessed November 12, 2020. 

3. Columbia University Irving Medical Center. Study finds evidence of neurobiological mechanism for hallucinations and delusions. News release. Medical Xpress. November 9, 2020. Accessed November 12, 2020. 

https://medicalxpress.com/news/2020-11-evidence-neurobiological-mechanism-hallucinations-delusions.html

Findings bring us closer to understanding schizophrenia that may enable clinicians to target symptoms.

Schizophrenia in the News 

All other clinicians either will receive a CME Attendance Certificate or may choose any of the types of CE credit being offered.

The goal of this activity is to inform readers about the possible connections between infertility and mental health disorders.

• Understand the prevalence of mood and anxiety disorders in women experiencing infertility and undergoing infertility treatment

• Identify patients who may need psychiatric support during infertility treatment

• Appreciate factors that may modulate vulnerability to stress, anxiety, and depression in the context of infertility and its treatment

• Identify appropriate treatment options for mood and anxiety disorders in women undergoing infertility treatment

This continuing medical education (CME) activity is intended for psychiatrists, psychologists, primary care physicians, physician assistants, nurse practitioners, and other health care professionals who seek to improve the care of patients with mental health disorders.

ACCREDITATION/CREDIT DESIGNATION/FINANCIAL SUPPORT

This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Physicians’ Education Resource®, LLC and 

. Physicians’ Education Resource®, LLC is accredited by ACCME to provide continuing medical education for physicians.

Physicians’ Education Resource®, LLC designates this enduring material for a maximum of 1.5 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

This activity is funded entirely by Physicians’ Education Resource®, LLC. No commercial support was received.

This CME activity may or may not discuss investigational, unapproved, or off-label use of drugs. Participants are advised to consult prescribing information for any products discussed. The information provided in this CME activity is for continuing medical education purposes only and is not meant to substitute for the independent clinical judgment of a physician relative to diagnostic or treatment options for a specific patient’s medical condition.

The opinions expressed in the content are solely those of the individual faculty members and do not reflect those of Physicians’ Education Resource®, LLC.

FACULTY, STAFF, AND PLANNERS’ DISCLOSURES

Elizabeth Clayton, Ruta Nonacs, MD, PhD, Linda L.M. Worley, MD, FACLP (external reviewer), the staff members of Physicians’ Education Resource®, LLC, and Psychiatric TimesTM have no relevant financial relationships with commercial interests.

Once you have read the article, please use the following URL to evaluate and request credit 

https://education.gotoper.com/activity/ptcme20dec

. If you do not already have an account with PER® you will be prompted to create one. You must have an account to evaluate and request credit for this activity.

Ms Clayton is an MD candidate (class of 2021) at Tufts University School of Medicine. Dr Nonacs is clinical assistant professor in the Department of Psychiatry at Massachusetts General Hospital and editor in chief at the MGH Center for Women’s Mental Health.

Difficulty with conceiving can have many psychological repercussions. Infertility is defined as the inability of a couple to conceive after 12 months of regular intercourse without the use of contraception in women aged 35 years or younger, or after 6 months in women aged 36 years or older. The Centers for Disease Control and Prevention (CDC) reports that 12% of women aged 15 to 44 years have difficulty getting pregnant or carrying a pregnancy to term (

). Some form of infertility was reported by 9% of men aged 25 to 44 years. In about 35% of couples 

, infertility was due to both male and female factors.

Infertility can have a profound impact on psychological well-being for both the individual and the couple. A woman may find herself feeling betrayed by her body and may be overcome by emotions, ranging from profound despair to anger and resentment, when a friend announces a pregnancy. Sexual intimacy can morph from an expression of closeness to a demand for conception. Each failed cycle is a multifaceted burden. In vitro fertilization (IVF) is rarely covered by insurance. Some individuals may even become suicidal with recurrent loss of pregnancy.

While we acknowledge that infertility and its treatment are physically and psychologically challenging, there is a paucity of research into the association between psychiatric illness and infertility (

). Additionally, we know little about the psychological impact of infertility and prolonged exposure to infertility treatment on mood and well-being. As the current research stands, it is unclear how mood and anxiety disorders impact fertility and if infertility and its treatment may lead to mood and anxiety disorders.

Impact of affective disorders on fertility and its treatment

There are conflicting data regarding the impact of depression and anxiety on the reproductive cycle. In one study, it was observed that depressive symptoms were not associated with changes in reproductive hormone levels,

 but other studies have found that self-reported levels of stress do impact hormone levels.

 In a group of young women aged 17 to 20 years,higher ratings of stress were associated with lower estradiol (but not testosterone or progesterone) concentrations. This finding is consistent with previous studies suggesting that prolonged perceived stress may lower overall estradiol production, thus inhibiting ovulation and suppressing reproduction.

Inflammation may also play an important role in infertility, and current research suggests that chronic inflammation may affect fertility and pregnancy outcomes. Chronic stress, depression, and anxiety have all been associated with inflammation and, therefore, may interfere with attempts to conceive. In a study of women and men undergoing infertility treatment, higher stress levels were associated with various markers of inflammation, including higher cervicovaginal inflammatory cytokines. These inflammatory markers were, in turn, associated with a decreased likelihood of achieving pregnancy through IVF.

It is likely that high levels of cumulative stress associated with recurrent depression and/or anxiety may affect multiple stages of fertilization. That said, normal levels of stress related to infertility treatment probably have minimal effects. A prospective study from 

 examined anxiety and stress levels in women and men pursuing infertility treatment before undergoing ovarian stimulation. The researchers found that neither partner’s level of treatment-related stress had an impact on the number of ovarian follicles greater than 16 mm, with ovarian follicle size being a predictor of IVF success.

Health care providers can reassure patients that neither partner’s situational stress will impact follicle stimulation. Additionally, it has been speculated that chronic stress impedes successful implantation, but difficulty with implantation can be overcome using IVF. Although more research is needed, IVF may be a reasonable recommendation for women with mood disorders who are experiencing infertility.

Although it is unclear whether depression affects fertility, it may have an impact on treatment with assisted reproductive technology (ART). Health care providers should be aware that women with depression are less likely to pursue infertility treatment. A recent prospective study of patients attending a fertility clinic found that women who screened positive for depression were about half as likely to initiate treatment for infertility compared with their nondepressed counterparts.

 Additionally, depression in women has been associated with higher ART dropout rates. One study found that couples with a clinically depressed female partner were 5 times more likely to discontinue treatment than couples with a nondepressed partner.

 Screening for depression is therefore important in couples pursuing infertility treatment, and extra care should be taken to provide appropriate support to patients seeking infertility treatment who screen positive for an 

Eating disorders and infertility treatment

Infertility and subfertility may occur in women with anorexia nervosa (AN), bulimia nervosa (BN), and binge eating disorder (BED). In women with active illness, amenorrhea and oligomenorrhea can compromise the likelihood of conception (

 irregularities occur most commonly in women with AN, with 39% to 42% experiencing amenorrhea (an absence of menstruation) and an additional 6% to 11% reporting oligomenorrhea (infrequent menstruation); however, 7% to 40% of women with BN report amenorrhea and 36% to 64% experience oligomenorrhea.

The strongest predictors of amenorrhea in women with eating disorders are low body mass index (BMI), low caloric intake, and higher levels of exercise. Weight restoration is the primary intervention for amenorrhea in women with eating disorders, although amenorrhea may persist even after normal weight has been restored. In addition, polycystic ovarian syndrome (PCOS) may be another factor contributing to menstrual irregularity in this population, as PCOS is common among women with BN and BED. In fact, one study reported polycystic ovaries in 75% of women with BN.

Women with a current eating disorder may experience fertility problems, especially if they have a low BMI and experience menstrual irregularity. However, data regarding the fertility of women with a history of an eating disorder have yielded mixed results. Many studies, including 2 large, population-based cohort studies, have 

 similar rates of successful pregnancy in women with a history of an eating disorder compared with women in the general population.

 At the same time, prospective data from the Avon Longitudinal Study of Parents and Children (ALSPAC) indicate that women with a history of AN or BN were more likely to take longer than 6 months to conceive and were more likely to have conceived with the aid of fertility treatment.

While we do not have detailed information on the impact of other psychiatric disorders (such as bipolar disorder and schizophrenia) on fertility, it should be noted that certain medications used to treat these disorders may cause menstrual irregularities, including amenorrhea, and may thus negatively affect fertility. For example, antipsychotic agents with strong antagonism of the dopamine D2 receptor, such as risperidone and older antipsychotics, increase levels of prolactin, causing hypogonadotropic hypogonadism and subsequent menstrual dysfunction.

Finally, drug and alcohol use disorders have well-documented effects on the fetus, but the effects on conception and implantation of an embryo are unclear. Studies have suggested that substance use disorder has a negative impact on female and male fertility, but more research is needed in this area.

 The majority of data have come from animal models. Studies in humans have been observational and are complicated by participants who use multiple substances and different routes of administration. Explicit associations between substance use and fertility is further confounded by lifestyle factors that often accompany substance use, such as overall unhealthy lifestyle, poor decision-making, and comorbid physical and mental health disorders.

Psychological impact of fertility treatment

The decision to begin ART can be very stressful for couples, and research has shown that stress may increase with each subsequent fertility treatment.

 However, distress can manifest at any point during ART. In a large Dutch study following couples experiencing infertility (who reported undergoing an average of 4.3 fertility treatments over 5 years), a passive-avoidant method of coping (eg, hoping for a miracle) was linked with psychological distress in women, and this effect increased over time. For men, this coping style led to increased marital distress.

 Women who perceived infertility as central to their identity, and who were resistant to realigning their goals, reported greater distress during fertility treatment.

 On the other hand, meaning-based coping strategies, learning to grow from a negative experience, and/or finding other goals in life were associated with decreased distress in women, but not in men. A woman’s use of meaning-based coping strategies also decreased marital stress for both partners.

 It is important to note that these studies are based in countries where fertility treatment is covered by insurance, which is rare in the United States. American couples undergoing ART have additional stressors, although they would also likely benefit from these coping strategies.

Protective factors have also been identified. For a woman, having a higher level of education and adequate social supports decreases distress during ART. For men, a problem-solving coping strategy was linked to a higher self-reported quality of life (QOL).

 In a study from Israel, where there is a social emphasis on having children, researchers observed that maintaining daily routines and making efforts to feel normal led to a higher QOL and better adjustment to fertility treatment.18 In another study, the Dyadic Adjustment Scale (DAS), a tool that measures relationship distress, was administered to couples currently undergoing fertility treatment. Higher dyadic adjustment was associated with better QOL and less psychological distress in both men and women undergoing ART. However, this protective effect was diminished when infertility persisted for longer than 3 years.

Although multiple studies have assessed psychological distress in couples undergoing treatment for infertility, far fewer have assessed the prevalence of clinically significant anxiety and depressive symptoms in this population. A large Danish study of couples undergoing ART found severe depressive symptoms in 11.6% of women and 4.3% of men.

 These symptoms correlated to an increase in infertility-related distress. However, there is considerable variation among studies with regard to rates of depression and anxiety in couples pursuing infertility treatment, which may reflect differences in type of ART, duration of infertility, number of failed cycles, cultural considerations, and methods used to assess symptoms.

According to another study, women who conceived through ART showed no difference in anxiety and depressive symptoms compared with pregnant women who conceived naturally. However, rates of depression and anxiety were higher in subfertile, nonpregnant women (57.6% and 15.7%, respectively).

 Comparisons between women undergoing repeated IVF cycles and first-time participants have suggested that ongoing treatment may lead to an increase in depressive symptoms, which may persist for 6 months after a failed ART trial.

Recent research also suggests that both women and men with a history of major depressive disorder (MDD) are more 

 to experience depressive symptoms during ART.

 In a prospective observational study of 25 women with a history of 

Matters around child-bearing bring up emotions ranging from joy and elation to profound despair, anger, and resentment. Psychiatrists are trained to recognize such issues.

Vol 37, Issue 12

A Recipe for Homemade Obesity: The Association Between Depression, Obesity, and Cognitive Deficits

Diverse Patients, Common Ground

Case-Based Psych Perspectives: Treating Schizophrenia in the Era of COVID-19

Schizophrenia and AUD

Schizophrenia in the News

The Intertwining Effect of Mood Disorders and Infertility

Lessons Learned From Treating COVID-Related Anxiety

An Optimistic Prognosis for 2021

Of Personas and Perfection—and Physician Suicide

A Dickens of a Year

Kindness, Anonymous Heroes, and Compassion