Examine the pathophysiology and comorbidities associated with bipolar disorder or schizophrenia

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Watch Jonathan Meyer, MD, talk about comorbidities and the pathophysiology of bipolar disorder or schizophrenia

Keep the Body in Mind: Looking at the Pathophysiology and Comorbidities Associated with Bipolar Disorder or Schizophrenia

Presented by Jonathan M. Meyer, MD,* clinical professor of psychiatry at University of California, San Diego.

*Dr. Meyer is a paid consultant of Alkermes, Inc.

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NARRATOR

Keep the Body in Mind: Looking at the Pathophysiology and Comorbidities Associated With Bipolar Disorder or Schizophrenia with Dr. Jonathan Meyer.

 

DR. MEYER

Hello and welcome to this non-CME, on-demand program sponsored by Alkermes, Incorporated.

I am Dr. Jonathan Meyer, a clinical professor in the department of psychiatry at the University of California, San Diego School of Medicine. I am a paid consultant for Alkermes, Incorporated.

Today we are going to talk about the pathophysiology and physical comorbidities reported in patients with bipolar disorder or schizophrenia, as well as the importance of managing the whole patient.

 

To begin, I would like to tell you about Carlos. He is a person living with schizophrenia, and has a story to share with us.

Let’s hear Carlos’ story directly from him.

 

ANA

My name is Ana, and my son, Carlos, is a person living with schizophrenia.

CARLOS

One of the features of these illnesses is that they can sometimes rob you of your self-awareness. So if you asked me during this time period what was going on I would have told you I was perfectly fine and nothing was happening. Even though by all objective measures my life was deteriorating. I was eating out of trashcans. I was smoking cigarettes off the ground. I definitely was, I think, coping in an unhealthy manner through substance use.

ANA

It’s vital for any care giver to have a very engaging relationship with the entire healthcare team.

CARLOS

Early on in my recovery, I was encouraged by both my provider and family to attend support groups.

ANA

The support group setting is important, and it’s vital to their recovery because it takes the fear away. I think family support is pivotal, and it’s one of the founding pillars of recovery. It’s where the love comes in.

CARLOS

I feel very fortunate to have my mother as an advocate for me throughout my recovery. My name is Carlos, and I’m a person living with schizophrenia.

DR. MEYER

Now that we heard Carlos’ story, let’s take a look at today’s objectives. The program objectives are three-fold. We will explore how serious mental illness, including bipolar disorder and schizophrenia, may affect the whole person. We will detail the pathophysiology of bipolar disorder and schizophrenia and a range of comorbidities that may occur. And, finally, we will identify opportunities for mental health providers to manage the whole patient.

 

Let’s begin by reviewing the prevalence of serious mental illness, or SMI.

 

The National Institute of Mental Health, or NIMH, defines SMI as a mental, behavioral, or emotional disorder resulting in serious functional impairment that substantially interferes with, or limits, one or more major life activities.

According to the NIMH, the estimated one-year prevalence of SMI in 2017 was approximately 4.5 percent among US adults.

If we examine bipolar disorder and schizophrenia more closely, we see the estimated one-year US adult prevalence of bipolar one disorder ranges from about 0.6 to 1.5 percent, based on estimates from 2011 and 2017. Differences in prevalence estimates across studies may be influenced by the design of the study, the criteria used from the Diagnostic and Statistical Manual of Mental Disorders, and the diagnostic interview tool used.

In 2018, the estimated one-year US adult prevalence of schizophrenia was estimated to range from about 0.25 to 0.64 percent. Precise prevalence estimates of schizophrenia are difficult to obtain due to clinical and methodological factors, such as the complexity of schizophrenia diagnosis, its overlap with other disorders, and varying methods for determining diagnoses.

 

Higher mortality risk has been observed in patients with SMI.

A 2017 observational study followed primary care electronic health records from 2000 to 2014 in UK patients with SMI, including 17,314 patients with bipolar disorder, 22,497 patients with schizophrenia, and 219,387 matched individuals without either diagnosis. Patients with bipolar disorder or schizophrenia had 1.77-fold or 2.08-fold increased risk of mortality compared with the general population, respectively.

In addition, a 2014 fact sheet from the World Health Organization suggested there is a 10- to 25-year life expectancy reduction in patients with psychosis, bipolar mood disorder, or moderate-to-severe depression.

 

Next, we’ll discuss excess deaths that have been observed in patients with bipolar disorder.

 

A 2001 analysis of 15,386 Swedish patients with bipolar disorder suggested respiratory diseases, accidents, suicide, and vascular diseases were among the most frequent causes of excess mortality compared with the general population from 1973 to 1995.

Excess mortality was calculated by subtracting the expected number of deaths from the observed number of deaths reported in the in-patient register and the national cause-of-death register in Sweden. Mortality ratios were calculated from the observed number of deaths divided by the expected number of deaths. The study was not powered for direct comparison among causes.

Across male and female patients with bipolar disorder, respiratory diseases, accidents, suicide, and vascular diseases resulted in approximately 153, 112, 634, and 700 excess deaths compared with the general population, respectively.

 

A similar analysis of 7,784 Swedes with schizophrenia in 2000 suggested the same four causes of excess mortality were among the most frequent compared with the general population from 1973 to 1995.

Across male and female patients with schizophrenia, respiratory diseases, accidents, suicide, and vascular diseases resulted in approximately 87 deaths, 67 deaths, 359 deaths, and 350 deaths, respectively.

 

Multiple studies have reported an increased prevalence of physical comorbidities—including infectious, respiratory, metabolic, and cardiovascular diseases—in patients with SMI, including bipolar disorder and schizophrenia, compared with the general population.

Let’s take a more detailed look at a few of those studies.

A 2011 review of publications from 1966 to August 2010 examined physical disease categories in patients with SMI, including bipolar disorder and schizophrenia, to identify prevalence figures. Among infectious diseases, patients with SMI were reported to have increased prevalence of HIV and hepatitis B and C. Among respiratory diseases, patients with SMI were reported to have increased prevalence of COPD and asthma. Among metabolic diseases, patients with SMI were reported to have increased prevalence of being overweight, obesity or abdominal obesity, metabolic syndrome, diabetes mellitus, and hyperlipidemia. We should note that the risk of obesity in persons with SMI varies by diagnosis. Among cardiovascular diseases, patients with SMI were reported to have greater prevalence of stroke, myocardial infarction, hypertension, and other cardiac and vascular diseases.

Likewise, a 2010 study of electronic health records system data from Kaiser Permanente of Northern California identified 20,308 adults with bipolar disorder and 4,782 adults with schizophrenia based on ICD-9 diagnosis. The study included 25,090 control patients without current or existing behavioral health diagnoses. It reported greater than 2 times the odds of stroke, obesity, hepatitis C, COPD, and pneumonia in both schizophrenia and bipolar disorder compared with matched controls.

A retrospective claims analysis from Wellmark Blue Cross/Blue Shield of Iowa examined 1,074 patients with schizophrenia or schizoaffective disorder and 726,262 controls from 1996 to 2001. Patients with schizophrenia were more likely than controls to have congestive heart failure, cardiac arrhythmias, peripheral vascular disorder, stroke, COPD, asthma, diabetes, obesity, and hepatitis.

In a fourth study, the Duke University Medical Center clinical database was used to categorize medical comorbidities of 1,379 patients treated with bipolar disorder from 2001 to 2002 through outpatient psychiatric clinics and to examine the prevalence of medical comorbidities. These comorbidities included cardiovascular disease, hypertension, COPD, asthma, diabetes, HIV infection, and hepatitis C infection.

Finally, a retrospective claims analysis from Wellmark Blue Cross/Blue Shield of Iowa examined the prevalence of medical conditions in 3,557 patients with bipolar disorder compared with 726,262 controls from 1996 to 2001. The conditions that were more likely to be observed in patients with bipolar disorder can be grouped into cardiovascular, metabolic, pulmonary, hematological, neurological, infectious, and endocrine.

 

NARRATOR

Schizophrenia: Potential Dysfunction Across Multiple Systems.

 

DR. MEYER

Let’s now look at the potential dysfunction that may be present across multiple systems in patients with schizophrenia based on evidence from antipsychotic-naive patients.

 

Schizophrenia may involve dysfunction across cardiometabolic, immune, and endocrine systems. Alterations in parameters across all of these systems have been observed in antipsychotic-naive patients with first-episode psychosis.

A 2018 systematic meta-review was conducted to observe CNS, immune, cardiometabolic and endocrine alterations in antipsychotic-naive, first-episode schizophrenia patients based on data from 6 studies.

Antipsychotic-naive patients with first-episode psychosis were observed to have elevated blood cytokine levels, specifically interleukin one beta, or I-L-one beta, a soluble form of interleukin 2 receptor, or s-I-L-two-R, interleukin six, or I-L-six, and tumor necrosis factor alpha, or T-N-F-alpha; cardiac disturbances, including raised triglycerides, and reduced HDL, total and LDL cholesterols; metabolic disturbances, including insulin resistance, elevated fasting glucose and insulin, elevated glucose following the oral glucose tolerance test, and increased oxidative stress; and endocrine disturbances, including elevated prolactin levels.

 

Let’s start by looking at how reduced adiponectin levels have been observed in patients with schizophrenia.

 

Adipose tissue is a major endocrine organ regulating whole body metabolism as well as inflammatory and immune responses.

Adiponectin, an adipokine hormone produced primarily by fat cells in adipose tissue, makes tissues more sensitive to insulin while low levels of adiponectin are associated with insulin resistance, as reported in reviews from 2003, 2012 and 2017.

Data from both animal and human studies also indicate that adiponectin has insulin-enhancing and anti-inflammatory actions.

The net effects of adiponectin activity are thought to provide protection from insulin resistance, type 2 diabetes, and coronary artery disease in humans.

The association between adiponectin and antipsychotic-naive schizophrenia is still unclear. Lower serum adiponectin levels have been detected in this subpopulation compared with healthy controls.

Lower adiponectin levels have also been observed in antipsychotic-prescribed patients with schizophrenia.

 

Elevated blood cytokines have been observed in patients with schizophrenia.

Immune activation may occur both peripherally and centrally in patients with schizophrenia.

A 2018 systematic meta-review noted that 4 studies examined immune profiles in antipsychotic-naive patients. These studies determined that elevated blood cytokine levels were seen in antipsychotic-naive, first-episode schizophrenia patients. These inflammatory cytokines include I-L-one beta, s-I-L-two-R, I-L-six, and T-N-F-alpha.

Elevated pro-inflammatory cytokines have been differentially associated with regional brain volume alterations, although correlations are inconsistent and further studies are required to clarify these alterations in the context of systemic inflammation in first-episode psychosis.

Adipose tissue also releases pro-inflammatory cytokines, including I-L-six and or T-N-F-alpha, which may contribute to insulin resistance.

There may be an imbalance between adiponectin and pro-inflammatory cytokines in patients with schizophrenia, contributing to a persistent cycle of obesity and inflammation.

In obesity, production of inflammatory cytokines from adipose tissue increases, causing inflammation.

C-reactive protein is a commonly used biomarker of inflammation in clinical practice that is directly modulated by I-L-six and I-L-one beta, and increased levels are associated with obesity, metabolic syndrome, and cardiovascular disease.

A meta-analysis of antipsychotic-free patients with first-episode psychosis, including patients with schizophrenia, schizophreniform, or schizoaffective disorder, observed an association between body mass index and higher levels of c-reactive protein.

 

Elevated prolactin levels have been observed in patients with schizophrenia.

Prolactin is a polypeptide hormone secreted from the anterior pituitary gland, and it is believed that prolonged hyperprolactinemia may be associated with sexual dysfunction, including amenorrhea and galactorrhea, breast cancer and an acceleration of osteoporosis in women, and a lack of libido and erectile dysfunction in men.

This 2016 systematic review and meta-analysis examined blood prolactin levels in antipsychotic-naive patients with schizophrenia and related disorders in comparison to controls. The meta-analysis included 7 studies with 141 male patients and 5 studies with 67 female patients.

Elevated prolactin levels were observed in both male and female antipsychotic-naive patients with schizophrenia and related disorders, including delusional disorder, brief psychotic disorder, schizophreniform disorder, schizophrenia, or schizoaffective disorder.

It is hypothesized that prolactin release may be increased in response to stress and be associated with hypothalamic-pituitary-adrenal axis, or HPA, activity.

 

NARRATOR

Schizophrenia: Pathophysiology.

 

DR. MEYER

As we look at the pathophysiology of schizophrenia, let’s begin by reviewing the CNS pathophysiology of schizophrenia and then discuss associated symptomatology.

 

If we focus on particular neurotransmitters, we see that several have been proposed to play a role in the pathophysiology of schizophrenia, including dopamine, serotonin, acetylcholine, gamma-amino-butyric acid, or GABA, and glutamate.

While neurotransmitter models of schizophrenia have historically attributed symptom development primarily to the dysregulation of the dopaminergic system, others are implicated, including the glutamatergic system.

The revised dopamine hypothesis of schizophrenia postulates that dopamine hyperactivity in the mesolimbic regions of the brain is associated with the positive symptoms of schizophrenia, while dopamine hypoactivity in the prefrontal cortex may be related to negative or cognitive symptoms.

The N-methyl-d-aspartate, or NMDA hypothesis of schizophrenia, postulates that dysregulated glutamatergic neurotransmission arising from NMDA receptor hypofunction could lead to the positive and negative symptoms and also cognitive impairment associated with schizophrenia.

 

To further understand the potential relationship between dopaminergic signaling and the symptoms of schizophrenia, let’s review how dopamine circuits may be associated with various functions.

 

Dopamine is synthesized in the brainstem substantia nigra and ventral tegmental area, and dopaminergic projections are divided into nigrostriatal, mesolimbic, and mesocortical pathways.

The mesolimbic circuitry, projecting from the ventral tegmental area to the ventral striatum, is considered to be part of the brain’s reward circuitry for motivation, pleasure, and reward, and is thought to have an important role in several emotional behaviors.

The mesocortical pathway projects to the prefrontal cortex, which is associated with regulation of emotion and affect, as well as cognitive and executive function.

The nigrostriatal pathway, projecting from the substantia nigra to the dorsal striatum, is part of the extrapyramidal nervous system and controls motor movements. Deficiencies in dopamine neurotransmission in this pathway result in parkinsonism and impaired goal-directed movements.

These associations are oversimplified, as every brain area has several functions and every function is distributed across several brain areas.

Still, the symptoms of schizophrenia are hypothesized to be related to disrupted dopaminergic brain circuits associated with some of these functions.

 

The positive symptoms of schizophrenia, including hallucinations and delusions, are associated with excess mesolimbic dopamine neurotransmission involving D2 receptors.

 

On the other hand, cognitive symptoms in schizophrenia may be associated with hypofunction of dopamine D1 receptor neurotransmission in the prefrontal cortex.

 

The negative symptoms of schizophrenia include anhedonia and lack of motivation, and may be associated with reduced dopamine D1 receptor activation in the prefrontal cortex.

 

In addition to being a negative symptom of schizophrenia, anhedonia, defined as diminished reward responsivity, has been frequently associated with depression in other psychiatric disorders, such as bipolar disorder, which suggests there may be common underlying deficits in reward system function among these conditions.

As previously mentioned, dopamine circuitry projecting to the ventral striatum is associated with reward.

 

Neural connectivity between the ventral striatum and major functional areas, including the default mode network, or DMN, was examined in relation to anhedonia from a large and heterogeneous sample of 225 adults with psychiatric conditions associated with reward abnormalities, including patients with schizophrenia and bipolar disorder. The DMN has been associated with internally directed modes of cognition, including reward valuation, and abnormal connectivity within the DMN has been reported in multiple psychiatric conditions where anhedonia is prominent.

Strength of neural functional connectivity in this study was evaluated from resting-state functional magnetic resonance imaging, and patients were assessed for reward sensitivity from the Reward subscale of the Behavioral Activation Scale, or BAS Reward. A lower score on the BAS Reward indicates greater reward deficits, or anhedonia.

As you can see here, greater reward deficits in patients with schizophrenia were associated with decreased connectivity between the ventral striatum and the default mode network.

The effects were consistent for subjects with bipolar disorder, schizophrenia, and psychosis risk groups, and the nucleus accumbens dysconnectivity may be associated with reward responsiveness deficits.

 

NARRATOR

Schizophrenia: Behavioral Risk Factors and Common Physical Comorbidities in Patients.

 

DR. MEYER

Now that we have reviewed the pathophysiology of schizophrenia, let’s focus on behavioral risk factors for common physical comorbidities in patients with schizophrenia, starting with substance use.

A number of theories suggest an association between substance use disorder and schizophrenia. Please note, this content is theoretical and more research is needed before the co-occurrence of schizophrenia and substance use disorder can be understood. I will first review three of those theories:

One theory is the diathesis-stress model, which suggests an interaction between neurobiological vulnerability and environmental stressors, including substance use, which may contribute to the onset of schizophrenia.

Another theory is the self-medication hypothesis, which suggests substance use is driven by a desire to lessen symptoms or decrease side effects of antipsychotic medication.

A third theory is the reward deficiency syndrome hypothesis, suggesting a common pathophysiology of overlapping neural circuits in both schizophrenia and substance use disorders, and that substance use may be related to a dysfunction of the brain reward circuit in patients with schizophrenia.

A unifying hypothesis may contain and further elucidate these existing theories, and it suggests there are many factors, including adolescent drug exposure and genetics, that may contribute to initiation and continued substance use in patients with schizophrenia. The interaction of these factors may lead to dysfunction within brain circuits involved in reward and motivation.

Mesocorticolimbic dopamine dysregulation is hypothesized to contribute to vulnerability to both the initiation and continued use of substances in patients with schizophrenia.

It is hypothesized that a hypersensitive dopamine system may contribute to vulnerability toward substance use.

According to this hypothesis, genetic risk or an early environmental insult may lead to a dysfunctional mesocorticolimbic brain reward circuit.

The dysregulated circuitry may lead to a high rate of initiation of substance use in a pre-psychotic individual. According to this hypothesis, it may trigger the onset of schizophrenia and also lead to continued substance use once it begins.

Even if the substance use does not begin prior to the onset of psychosis, this hypothesis suggests that the dysregulated circuitry may lead to initiation of substance use and continued use.

Substance use may precede or follow the onset of schizophrenia, and it is unclear whether the epidemiology of substance use or schizophrenia comes first.

As a reminder, this content is theoretical and more research is needed before the co-occurrence of schizophrenia and substance use disorder can be understood.

 

Studies have reported greater odds or risk of infectious diseases in patients with schizophrenia with co-occurring substance use disorder.

 

A 2006 study using the Veterans Affairs 20 database in the Northwest US collected data from 293,445 patients between January 1998 and December 2003 for hepatitis C virus, or HCV, laboratory results. The study included 39,922 patients with substance use disorder, 4,644 patients with schizophrenia or schizoaffective disorder diagnosis, and 4,192 patients with co-occurring schizophrenia and substance use disorder.

Patients were considered positive for HCV if they had a positive HCV antibody test, a detectable HCV viral load by polymerase chain reaction, a positive HCV recombinant immunoblot assay, or an identifiable HCV genotype.

Patients with schizophrenia and substance use disorder had greater odds of hepatitis C than those without substance use disorders, but patients with schizophrenia or schizoaffective disorder had significantly higher risk of HCV infection regardless of whether they had co-occurring substance use disorders.

Compared with controls, patients with substance use disorder, schizophrenia, and co-occurring schizophrenia and substance use disorder were approximately 7 times, 2 times, and 8 times as likely to have HCV infection, respectively.

A 2015 population-based cohort study using the Danish nationwide registries investigated the effect of schizophrenia on risk of HIV infection in 2,658,662 patients born in Denmark between 1955 and 1995.

Data were stratified by 148,107 patients with history of substance misuse or 2,510,555 patients with no history of substance use disorder.

Of the 1,639 participants diagnosed with HIV during follow-up, 49 patients had schizophrenia and a history of substance misuse, representing an approximate 1.75 times greater risk of HIV.

Patients with schizophrenia, but with no history of substance misuse, did not have a significantly increased risk of HIV infection.

 

Tobacco use is another behavioral risk factor more common in patients with schizophrenia.

A 2012 meta-analysis examined the prevalence and odds of daily tobacco use in patients with first-episode psychosis, including patients with first-episode schizophrenia, schizoaffective disorder, other schizophrenia-spectrum disorder, or affective psychosis, at initial treatment for psychosis.

The analysis determined 58.9% of patients smoked tobacco prior to treatment, and patients with first-episode psychosis were 6.04 times as likely to use tobacco compared with age- and gender-matched controls.

This analysis was consistent with a systematic review of 42 studies from 20 nations that determined patients with schizophrenia are 6 times as likely to use tobacco than the general population.

The study determined patients with schizophrenia, on average, initiate tobacco use 5.3 years prior to the onset of psychosis.

A 2014 study compared 28 smokers with schizophrenia or schizoaffective disorder with 27 control smokers without psychiatric illness on cigarette craving and nicotine withdrawal symptom severity during a 72-hour smoking abstinence period.

All participants smoked 20 to 50 cigarettes per day, had Fagerstrom Test for Nicotine Dependence scores greater than or equal to 6, and indicated that they wanted to quit smoking.

After abstinence was verified, participants completed craving and nicotine withdrawal measures, including the Questionnaire on Smoking Urges-brief form, or QSU brief, to assess cigarette craving.

The QSU F1 factor represents desire to smoke, while the QSU F2 factor, displayed on the graph, represents anticipation of relief of negative affect and urgent desire to smoke.

QSU F1 and QSU F2 scores were significantly higher in smokers with schizophrenia than control smokers over the 72-hour abstinence period.

The QSU F2 score remained significant when baseline scores that predicted for craving and nicotine withdrawal symptoms during abstinence were included as a covariate.

There are many hypotheses for higher prevalence of smoking in patients with schizophrenia, but increased negative symptomatology, deficits in reward processing, and alterations in reward-related brain circuitry may be related to increased smoking.

 

Higher odds of respiratory diseases have been observed in patients with schizophrenia, and a 2004 survey study examined how tobacco smoking may contribute.

This study interviewed patients receiving psychiatric care in Maryland, including 100 patients with schizophrenia or schizoaffective disorder, for the presence of medical conditions and health behaviors, such as smoking.

Smoking status was measured by asking patients if they had ever smoked 100 cigarettes in their lifetimes.

Responses from patients with schizophrenia were compared with individuals from national survey data sets and stratified into age-race-gender groups.

Patients with schizophrenia were observed to have 2.43, 3.69, and 9.14 times the odds of asthma, chronic bronchitis, and emphysema, respectively.

When controlling for smoking, increased odds for respiratory diseases were reduced but not eliminated, resulting in adjusted odds ratios of 2.23, 3.13, and 7.22 for asthma, chronic bronchitis, and emphysema, respectively.

 

Let’s talk a little bit more about how dopamine signaling is hypothesized to be related to altered reward anticipation and dysregulated energy allocation in patients with schizophrenia. This content is theoretical and more research is needed to confirm the hypothesis we’re about to discuss.

The current understanding of the neuroscientific basis of weight gain in schizophrenia is limited. One hypothesis is altered reward anticipation related to striatal dopaminergic dysregulation may be related to the high prevalence of weight gain and obesity, but our understanding is limited.

Decreased striatal dopamine signaling may be associated with reduced sensitivity to natural rewards and lead to compensatory, compulsive eating in both obesity and schizophrenia.

This hypothesis stems from different lines of evidence.

First, reduced striatal activation that may be associated with reward anticipation has been observed in antipsychotic-naive patients with schizophrenia.

Functional MRI experiments probing reward anticipation in the ventral striatum with a monetary incentive delay task have observed decreased striatal activation in antipsychotic-naive patients with schizophrenia.

While striatal dopamine signaling may correlate with the magnitude of a predicted reward from conditioned stimulus, which may allow an individual to prepare for the receipt of reward and approach it, the dopaminergic signaling may also encode how the experience of reward differs from the anticipated reward.

Although the link between altered reward anticipation and weight gain is unclear in schizophrenia, it parallels altered reward anticipation and reduced striatal dopamine neurotransmission that has been observed in pathologically obese individuals.

Low dopamine levels associated with schizophrenia may also result in dysregulated energy allocation.

According to this hypothesis, dopamine may provide a balance between exploration and exploitation of an energy source related to energy expenditure, and this role may have implications for 2 fundamental decisions concerning weight gain.

The first is how much energy an organism needs to expend to obtain energy from a known, current food source versus an unknown, future food source.

The second is how thrifty an organism needs to be in using available energy.

According to this model, low levels of dopamine that may be associated with schizophrenia may result in increased exploitation rather than exploration, or low energy expenditure. In this manner, schizophrenia may be related to dysregulated energy allocation.

This content is theoretical and more research is needed to confirm this hypothesis.

 

There may be several risk factors related to increased cardiovascular disease in patients with schizophrenia, several of which have already been discussed during this presentation.

A 2009 statement from the European Psychiatric Association, supported by the European Association for the Study of Diabetes and the European Society of Cardiology, suggested several potential reasons for increased cardiovascular disease among patients with serious mental illness, including schizophrenia.

These include increased likelihood of metabolic risk factors, including diabetes, hypertension, dyslipidemia, and obesity.

Other factors may be unhealthy lifestyle, including poor diet and sedentary behavior, and increased likelihood of smoking.

Also, many patients with SMI, including schizophrenia, have less access to healthcare and cardiovascular risk screening and prevention.

A 2014 nonsystematic review of cardiovascular disease epidemiology in patients with schizophrenia aligns with these possible factors, suggesting increased prevalence of metabolic syndrome, including abdominal obesity, elevated blood pressure, dyslipidemia, and insulin resistance.

This review also identified lifestyle factors, including smoking, sedentary behavior, and unhealthy diets that are reported to be more prevalent in patients with schizophrenia.

 

NARRATOR

Bipolar Disorder: Potential Dysfunction Across Multiple Systems.

 

Let’s now examine the potential dysfunction in patients with bipolar disorder.

 

Bipolar disorder, a complex disorder that affects brain functioning, may involve dysfunction across several systems that may contribute to its early and severe medical burden.

Bipolar disorder may involve dysfunction across metabolic, immune, and endocrine systems.

 

A 2002 study observed increased prevalence of type 2 diabetes in patients with bipolar one disorder compared with national norms, independent of psychotropic medication.

This study was a retrospective chart review of 243 older patients aged 50 to 74 years who were hospitalized at the University of Maryland medical center with a diagnosis of unipolar major depression, bipolar one disorder, schizoaffective disorder, schizophrenia, or dementia. The 90 patients with bipolar one disorder were found to have rates of diabetes significantly higher than national norms, suggesting an intrinsic relationship between abnormal glucose metabolism and bipolar one disorder.

In a 2008 study, greater weight and BMI were observed in drug-naive patients with bipolar disorder compared with controls who were psychiatric patients with obsessive compulsive disorder.

In this study, weight and height were retrospectively obtained from the charts of 76 antipsychotic-naive patients with a diagnosis of bipolar one or bipolar two disorder. For comparison, 65 patients with obsessive compulsive disorder were selected as a reference group and investigated with the same methodology to estimate their BMI. Mean weight and mean BMI were found to be higher in patients with bipolar disorder.

There is a need, however, for prospective studies to further evaluate these observations.

 

A 2015 study of 30 patients with bipolar disorder assessed severity of manic episodes from the Young Mania Rating Scale and measured plasma cytokine levels before and after treatment with an antipsychotic and mood stabilizer.

Before treatment, plasma levels of I-L-six, T-N-F-alpha, and interferon-gamma were higher in patients with bipolar disorder compared with healthy controls. Serum I-L-six to I-L-four, T-N-F-alpha to I-L-four, I-F-N-gamma to I-L-four, and I-F-N-gamma to I-L-ten ratios were higher in untreated patients with bipolar disorder compared with healthy controls.

During 6 weeks of follow-up, patients received treatment without randomization, with all combinations of treatment consisting of a mood stabilizer and antipsychotic, and plasma levels of I-L-six, I-L-ten, T-N-F-alpha and I-F-N-gamma were lower after treatment.

Serum I-L-six to I-L-four, T-N-F-alpha to I-L-four, I-F-N-gamma to I-L-four, and I-F-N-gamma to I-L-ten ratios were significantly decreased in patients after treatment. After treatment, I-L-six to I-L-four and T-N-F-alpha to I-L-four ratios were significantly higher in patients with bipolar disorder compared with healthy controls’ I-F-N-gamma to I-L-four and I-F-N-gamma to I-L-ten ratios, but I-F-N-gamma to I-L-four and I-F-N-gamma to I-L-ten ratios were similar to healthy controls.

 

Finally, let’s review an endocrine disturbance in patients with bipolar disorder.

 

Cortisol, a glucocorticoid product of the HPA axis, may be elevated following exaggerated release of corticotropin-releasing factor and greater adrenocorticotropic hormone, or ACTH, secretion in patients with bipolar disorder, as reported in a 2014 review.

Glucocorticoid receptors may have diminished sensitivity, possibly due to elevated inflammatory cytokines, resulting in dysregulated feedback regulation on the HPA axis and immune system.

A 2016 study consisted of a systematic review of stress reactivity, genetic, molecular, and neuroimaging studies related to HPA axis activity in bipolar disorder.

The systemic review suggested the role of abnormal HPA axis activity in the pathophysiology of bipolar disorder is unclear, but associations between HPA axis activity and neural structural alterations have been observed in drug-free patients.

The study also consisted of a meta-analysis of 41 case-control studies of 1,069 patients with bipolar disorder and 1,836 healthy controls that examined indices of HPA axis activity, including studies that reported data on basal cortisol, post-dexamethasone cortisol, ACTH, and corticotropin-releasing hormone.

The meta-analysis revealed patients with bipolar disorder had increased levels of basal and post-dexamethasone cortisol and ACTH compared with controls, and cortisol levels were positively associated with the manic phase, suggesting that abnormalities of HPA axis activity might change with phase of illness.

The percentage of medication-free patients was not a significant factor influencing the difference in basal cortisol levels between patients with bipolar disorder and controls, but the percentage of patients receiving antipsychotics was associated with a reduction of the effect size.

A 2014 meta-analysis of 19 studies that included 704 treated and medication-naive patients with bipolar disorder revealed increased levels of morning cortisol compared with controls.

There were no significant differences in effect size among medicated or medication-naive bipolar disorder patients based on a between-group comparison of medication subgroups.

 

NARRATOR

Bipolar Disorder: Pathophysiology, Behavioral Risk Factors, and Common Physical Comorbidities.

 

DR. MEYER

Abnormalities in dopamine and glutamate signaling have been found across states of bipolar disorder.

The dopamine hypothesis of bipolar disorder has been a theory of the pathophysiology of both manic and depressive phases of the illness for over 4 decades.

It suggests opposite changes in dopaminergic function underlie the opposing affective poles of the disorder, with hyperdopaminergia during mania versus hypodopaminergia associated with depression.

Additionally, the effects of dopamine may be mediated in part by glutamatergic signals in the prefrontal cortex.

This content is theoretical and more research is needed to confirm this hypothesis for bipolar disorder.

 

Looking at the dopamine pathways, evidence from pharmacologic and imaging studies suggest a hyperactive dopaminergic network underlies mania in bipolar disorder.

 

Interestingly, the evidence for hyperactivity associated with mania spans the ventral striatum, dorsal striatum, and prefrontal cortex.

In vivo imaging studies suggest psychotic symptoms in mania in patients with bipolar disorder may be associated with dopaminergic dysfunction, including elevated density of dopamine D2 receptors in dorsal striatum.

fMRI studies that used reward tasks in patients with bipolar disorder suggest abnormal reward-related neural activity in the ventral striatum and frontal cortex in patients with bipolar disorder with mania, including elevated frontal cortex activity during cued reward anticipation, and abnormally elevated activity within the ventral striatum during reward anticipation, reward consumption, and to reward-predictive cues.

Pharmacologic studies have observed mania-like symptoms following administration of dopamine agonists or psychostimulants in healthy volunteers and euthymic patients with bipolar disorder.

This content is theoretical and more research is needed to confirm this hypothesis.

 

Let’s turn our attention to behavioral risk factors for common physical comorbidities in patients with bipolar disorder, starting with substance use.

 

A 2008 study using the Veterans Affairs 20 database in the Northwest US collected data from 325,410 patients between January 1998 and December 2004 for hepatitis C virus, or HCV, laboratory results, including 37,970 patients with substance use disorder, 5,026 patients with bipolar disorder, and 4,724 patients with co-occurring bipolar disorder and substance use disorder.

Patients were considered positive for HCV if they had a positive HCV antibody test, a detectable HCV viral load by polymerase chain reaction, a positive HCV recombinant immunoblot assay, or an identifiable HCV genotype.

Compared with controls, patients with bipolar disorder, substance use disorder, and co-occurring bipolar disorder and substance use disorder had 1.31-fold, 4.86-fold, and 5.46-fold increase in the relative risk of HCV infection, respectively.

 

Higher odds of respiratory diseases have been observed in patients with bipolar disorder, and a 2004 survey study examined how tobacco smoking may contribute.

The study interviewed patients receiving psychiatric care in Maryland, including 100 patients with affective disorders, for the presence of medical conditions and health behaviors, such as smoking.

Half of the study group with affective disorders had major depression and half had bipolar disorder.

Smoking status was measured by asking patients if they had ever smoked 100 cigarettes in their lifetimes.

Responses from patients with affective disorders were compared with individuals from national survey data sets and stratified into age-race-gender groups.

Patients with affective disorders were observed to have 2.56, 4.57, and 4.19 times the odds of asthma, chronic bronchitis, and emphysema, respectively.

When controlling for smoking, increased odds for respiratory diseases were reduced but not eliminated, resulting in adjusted odds ratios of 2.46, 4.15, and 3.58 for asthma, chronic bronchitis, and emphysema, respectively.

 

Patients with bipolar disorder experienced increased odds for cardiovascular comorbidities.

A 2017 study of electronic health records system data from Kaiser Permanente of Northern California was conducted to identify 20,308 adults with ICD-9 diagnosis of bipolar disorder and 25,090 control patients without current or existing behavioral health diagnoses.

The study identified patients with bipolar disorder had 1.65 and 2.58 times the odds for hypertension and stroke, respectively, compared with controls.

 

NARRATOR

Opportunities for Mental Health Providers to Manage the Whole Patient.

 

DR. MEYER

We have now discussed physical comorbidities and potential dysfunction across multiple systems in patients with bipolar disorder or schizophrenia. What opportunities are there that could help manage the whole patient?

 

One suggested strategy is sharing electronic health records between physical and mental health care systems.

It is suggested that providers caring for people with SMI advocate for sharing electronic health records between public mental and physical health systems. Reliable capture of diagnostic information, laboratory values, demographics, and nonpharmacologic interventions is often inconsistent across physical and mental health care system databases.

Focusing on enhancing tobacco smoking cessation efforts, behavioral interventions include motivational interviewing and cognitive behavioral therapy, and they have shown promise for smokers with SMI.

Strategies for promoting integration of care include co-location of primary care providers in community mental health clinics to serve patients who are too psychotic or disorganized to access care in traditional primary care clinics. Many primary care providers are unaware of monitoring recommendations, and education for primary care providers about monitoring guidelines is suggested by the literature.

For patients who show worsening from screening, referral to a health care professional or program with expertise may be appropriate.

Finally, professional guidelines recommend that patients receive appropriate baseline screening and ongoing monitoring, and that clinicians also encourage patients to monitor themselves.

Other strategies addressed in monitoring guidelines include education for patients, family, and caregivers.

Any chosen strategy for improving patient care should be tailored to the individual patient.

 

The 2020 APA practice guideline for schizophrenia suggests patients with SMI, and schizophrenia in particular, may more frequently experience a variety of health conditions, including, but not limited to, cancer, cardiovascular disease, obesity, metabolic syndrome, diabetes, hepatitis C infection, HIV infection, sleep apnea, and poor oral health.

The APA practice guideline for schizophrenia suggests physicians should discuss relevant physical and laboratory assessments that may be needed with their patients as part of initial evaluation and follow-up assessment.

Note that the APA published these guidelines with a statement that they are undergoing copyediting and that the final version is expected to be released in summer 2020.

 

As we close today’s program, let’s review a summary of what we’ve discussed.

 

The pathophysiology of bipolar disorder or schizophrenia may include dysfunction across several neurotransmitter systems.

However, dysfunction and comorbidities across several non-CNS systems have also been observed.

There is an opportunity to improve whole patient care through comprehensive management of comorbidities and behavioral risk factors that may be present in patients living with bipolar disorder or schizophrenia.

 

I also wanted to let you know that on this website there are other resources, including a version of these slides for download.

 

This concludes our program today. Thank you for joining us, and we hope this presentation has been informative to you.

Serious mental illness (SMI) results in functional impairment

According to the National Institutes of Mental Health (NIMH), SMI is a mental, behavioral, or emotional disorder resulting in serious functional impairment that substantially interferes with or limits one or more major life activities.1

But it is not just the psychiatric component of SMI that affects patients. A range of common physical comorbidities and higher mortality risk have been observed in patients with SMI.2

Patients with serious mental illness (SMI) may experience a range of common physical comorbidities

Studies have reported an increased prevalence of several physical comorbidities in patients with SMI, including bipolar disorder and schizophrenia. The following physical illnesses and disease categories were consistently reported to be more common compared with the general population2-6:

Infections

  • HIV
  • Hepatitis B/C

Cardiovascular

  • Hypertension
  • Stroke

COPD=chronic obstructive pulmonary disease.

Not an actual patient.

COPD=chronic obstructive pulmonary disease.

Not an actual patient.

A woman surrounded by small images of the heart, liver, lungs, and kidneys. Descriptions of the comorbidities associated with each organ are included: cardiovascular diseases (heart), infectious diseases (liver), respiratory diseases (lung), and metabolic diseases (kidneys).

Respiratory

  • COPD
  • Asthma

Metabolic

  • Diabetes
  • Obesity
  • Metabolic
    syndrome

Higher mortality risk has been observed in patients with serious mental illness

Higher mortality risk

In a 2017 observational study, patients diagnosed with bipolar disorder or schizophrenia had an increased risk of mortality compared to the general population (1.77 times greater for bipolar disorder and 2.08 times greater for schizophrenia).7†
 

1.77x
Risk for
bipolar disorder
2.08x
Risk for
schizophrenia

Reduced life expectancy

A 2014 fact sheet from the World Health Organization (WHO) suggested there is a 10-25 year life expectancy reduction in patients with severe mental disorders.8‡

10-25
Years

This study was a review of primary care electronic health records in patients in the United Kingdom.

Based on a 2014 WHO information sheet that refers to patients with psychosis, bipolar mood disorder, and moderate-to-severe depression.

Increased mortality has been observed in patients with bipolar disorder and schizophrenia

Bipolar disorder and schizophrenia mortality statistics have been compiled using an analysis of patients with bipolar disorder (n=15,386) and patients with schizophrenia (n=7,784) in Sweden. This analysis suggested respiratory diseases, accidents, suicide, and vascular diseases were among the most frequent causes of increased mortality compared with the general population from 1973–1995.9-11

Increased mortality in patients with bipolar disorder

Excess deaths
The X-axis of a bar graph that illustrates the increased mortality observed in a Swedish study due to respiratory and vascular disorders, and due to accidents and suicide, among patients with bipolar disorder as compared with the general population

Respiratory

Accidents

Suicide

Vascular

Increased mortality in patients with schizophrenia

Excess deaths
The X-axis of a bar graph that illustrates the increased mortality observed in a Swedish study due to respiratory and vascular disorders, and due to accidents and suicide, among patients with schizophrenia as compared with the general population

Respiratory

Accidents

Suicide

Vascular

These were the 4 largest determined causes out of 15 causes of increased mortality, calculated by subtracting the expected number of deaths from the observed number of deaths reported in the in-patient register and the national cause-of-death register in Sweden; the study was not powered for direct comparison among causes or between patient groups.

Mental health providers have opportunities to help manage the whole patient with serious mental illness

There are opportunities that could help to improve whole-patient care through comprehensive management of comorbidities and behavioral risk factors that may be present in patients living with bipolar disorder or schizophrenia. These include the following strategies:

Icon consisting of a laptop computer

Sharing electronic health records between physical and mental health care systems, including reliable capture of diagnostics, laboratory values, demographics, and nonpharmacologic interventions12

Square icon of a lit cigarette emitting smoke

Enhancing tobacco smoking cessation efforts; eg, with behavioral interventions and pharmacologic smoking cessation options12

Icon consisting of 3 figures standing around a table

Promoting integration of care; eg, through co-location of primary care providers in community mental health clinics12

Icon consisting of electrocardiogram data superimposed on a heart located above the palm of a hand

Regular monitoring, including appropriate baseline screening and ongoing monitoring by clinicians and patients themselves13

Icon consisting of a computer monitor that displays a heart with superimposed electrocardiogram data

Referral to specialized services (healthcare professional or program with expertise), for patients who show worsening conditions from screening13

2020 APA Practice Guideline recommends ongoing monitoring of physical conditions

The 2020 American Psychiatric Association (APA) Practice Guideline for the Treatment of Patients with Schizophrenia suggests patients with serious mental illness, and schizophrenia in particular, may more frequently experience a variety of health conditions. These include, but are not limited to, cancer, cardiovascular disease, obesity, metabolic syndrome, diabetes mellitus, hepatitis C and HIV infections, sleep apnea, and poor oral health.14§

The guideline suggests physicians should discuss with their patients relevant physical and laboratory assessments that may be needed as part of initial evaluation and follow-up assessment.

Images of the heart, the liver, the lungs, the kidneys, the teeth, and the immune system.

§The APA published this guideline with a statement that it is undergoing copyediting and that the final version is expected to be released summer 2020.

BIPOLAR DISORDER BIPOLAR DISORDER
Comorbidities and
Pathophysiology

Not an actual patient.

SCHIZOPHRENIA
Comorbidities and
Pathophysiology

Not an actual patient.

Upcoming events related to bipolar disorder and schizophrenia

AACP - American Academy of Clinical Psychiatrists

Arlington, VA | 6/5/20 - 6/6/20

APNA - American Psychiatric Nurses Association

Reston, VA | 6/11/20 - 6/14/20

USPC - US Psych Congress Annual Congress - Fall

Nashville, TN | 9/10/20 - 9/13/20

APNA - American Psychiatric Nurses Association

Lake Buena Vista, FL | 9/30/20 - 10/3/20

NEI - Neuroscience Education Institute - Fall

Colorado Springs, CO | 11/5/20 - 11/8/20

AACP - American Academy of Clinical Psychiatrists

Las Vegas, NV | 12/6/20 - 12/8/20

Due to the COVID-19 pandemic, dates are subject to change or cancellation.

Resources

Support organizations and advocacy groups for patients with bipolar disorder or schizophrenia

Support and information are available from many organizations and advocacy groups for bipolar disorder and schizophrenia. Below is a partial list of organizations that provide information and support for healthcare professionals, caregivers, and patients with serious mental illness.

These links are provided for informational purposes only; they do not constitute an endorsement by Alkermes, Inc. Alkermes, Inc. is not responsible for the content of these third-party sites.

Stay informed on Keep the Body in Mind

Continue to receive information on the pathophysiology of and comorbidities associated with bipolar disorder or schizophrenia from KEEP THE BODY IN MIND.

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References: 1. Mental illness. National Institute of Mental Health Web site. https://www.nimh.nih.gov/health/statistics/mental-illness.shtml#part_154788. Accessed February 26, 2020. 2. Bahorik AL, Satre DD, Kline-Simon AH, Weisner CM, Campbell CI. Serious mental illness and medical comorbidities: Findings from an integrated health care system. J Psychosom Res. 2017;100:35-45. 3. De Hert M, Correll CU, Bobes J, et al. Physical illness in patients with severe mental disorders. I. Prevalence, impact of medications and disparities in health care. World Psychiatry. 2011;10(1):52-77. 4. Carney CP, Jones L, Woolson RF. Medical comorbidity in women and men with schizophrenia: a population-based controlled study. J Gen Intern Med. 2006;21(11):1133-1137. 5. Beyer J, Kuchibhatla M, Gersing K, Krishnan KR. Medical comorbidity in a bipolar outpatient clinical population. Neuropsychopharmacology. 2005;30(2):401-404. 6. Carney CP, Jones LE. Medical comorbidity in women and men with bipolar disorders: a population-based controlled study. Psychosom Med. 2006;68(5):684-691. 7. Hayes JF, Marston L, Walters K, King MB, Osborn DPJ. Mortality gap for people with bipolar disorder and schizophrenia: UK-based cohort study 2000-2014. Br J Psychiatry. 2017;211(3):175-181. 8. Mental disorders information sheet. World Health Organization. https://www.who.int/mental_health/management/info_sheet.pdf. Accessed February 26, 2020. 9. Osby U, Brandt L, Correia N, Ekbom A, Sparen P. Excess mortality in bipolar and unipolar disorder in Sweden. Arch Gen Psychiatry. 2001;58(9):844-850. 10. Weiner M, Warren L, Fiedorowicz JG. Cardiovascular morbidity and mortality in bipolar disorder. Ann Clin Psychiatry. 2011;23(1):40-47. 11. Osby U, Correia N, Brandt L, Ekbom A, Sparen P. Mortality and causes of death in schizophrenia in Stockholm county, Sweden. Schizophr Res. 2000;45(1-2):21-28. 12. Mangurian C, Newcomer JW, Modlin C, Schillinger D. Diabetes and cardiovascular care among people with severe mental illness: a literature review. J Gen Intern Med. 2016;31(9):1083-1091. 13. American Diabetes Association. Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care. 2004;(2)27:596-601. 14. Practice Guideline for the Treatment of Patients with Schizophrenia (Dec 2019). American Psychiatric Association. https://www.psychiatry.org/File%20Library/Psychiatrists/Practice/Clinical%20Practice%20Guidelines/APA-Draft-Schizophrenia-Treatment-Guideline-Dec2019.pdf. Accessed February 26, 2020.