Comorbidity

Schizophrenia, although a disabling disorder in itself, is associated with a host of comorbidities that further burden the patient.^{[APA, 2013; Buckley et al., 2009; Tsai & Rosenheck, 2013]} These include psychiatric and somatic conditions.^{[Buckley et al., 2009; Tsai & Rosenheck, 2013; Leucht et al., 2007; APA, 2013]}

The burden of comorbidity associated with schizophrenia means that it is important to focus on raising the awareness of physicians about the association between schizophrenia and other physical illness, and ensuring that psychiatrists are also skilled in the diagnosis and treatment of non-psychiatric conditions.^{[Leucht et al., 2007]}
 

The correction of the results for potentially confounding variables in this study was an important control step.^{[Crump et al., 2013]} The variables that were adjusted for included: age, marital status, education level, employment status, and income.^{[Crump et al., 2013]} Separately, the mediating effect of substance use was modelled, by including in the calculations any diagnosis of alcohol-use disorder or substance-use disorders (according to ICD-10 codes).^{[Crump et al., 2013]} 

The study also analysed all-cause mortality over the seven years of the study, from January 2003 to December 2009.^{[Crump et al., 2013]} The association between schizophrenia and all-cause mortality was stronger among women, the employed, and those without substance-use disorders.^{[Crump et al., 2013]} Schizophrenia was strongly associated with an elevated mortality, the leading causes of which were ischaemic heart disease, and cancer.^{[Crump et al., 2013]}
 

The diagnostic criteria for schizophrenia specify negative and cognitive symptoms.^{[APA, 2013, pgs. 99 & 101]} These include diminution in aspects of memory, executive functioning, and processing.^{[APA, 2013, pg. 101]} Although an aspect of schizophrenia, it is noted that the cognitive dysfunction persists during periods when other symptoms are in remission, and so cognitive dysfunction can be considered alongside other persisting comorbidities.^{[APA, 2013, pg. 101]}

Major depressive disorder (MDD) is characterised by a period of at least two weeks during which an individual displays either low mood, or diminished interest or pleasure.^{[APA, 2013, pg. 163]} There is a collection of associated symptoms, some of which must also be present, that constitute the diagnostic criteria for MDD, including weight changes, insomnia, psychomotor changes, fatigue, feelings of worthlessness, cognitive dysfunction, and recurrent thoughts of death.^{[APA, 2013, pg. 163]}

As is noted on the slide, some of the diagnostic criteria for schizophrenia overlap with those for MDD, particularly MDD with psychotic or catatonic features.^{[APA, 2013]} To distinguish the two, the temporal relationship between the mood disturbance and the psychosis should be considered; if the delusions or hallucinations occur exclusively during a depressive episode, then the diagnosis is MDD with psychotic features (or bipolar with psychotic features, if that diagnosis more accurately reflects the symptoms).^{[APA, 2013, pg. 104]}
 

Bipolar disorder is a manic–depressive illness, whereby individuals experience periods of depression characterised by low mood, and mania characterised by elevated, expansive, or irritable mood.^{[APA, 2013, pg. 124]} Bipolar disorder must be distinguished from schizophrenia, and other psychotic disorders.^{[APA, 2013]} Schizophrenia is characterised by psychotic symptoms that occur in the absence of predominant mood symptoms, whereas in bipolar disorder these psychotic symptoms occur exclusively during a depressive or a manic episode.^{[APA, 2013, pg. 104]}
 

The patient survey described on slide recruited 15 patients with a psychotic disorder, 8 of whom were diagnosed with schizophrenia.^{[Faulkner et al., 2017]} Semi-structured interviews were conducted, lasting between 30 and 110 minutes, focussing on the patient’s experiences of sleep, and how the sleep changes affected them.^{[Faulkner et al., 2017]} The interviews identified six main themes, which were expanded upon in the publication:^{[Faulkner et al., 2017]}

1. Sleep priorities: sleep quality and sleep maintenance
2. Loss of normality
3. Knocking yourself out
4. Priorities and life goals: daytime functioning
5. Sleep as an escape: surviving
6. Attitudes to non-pharmacological interventions: imperceptibility of gradual effects.

Fear is a normal response to certain stimuli; it is an emotional response to either a real or a perceived imminent threat; anxiety is simply anticipation of that future threat.^{[APA, 2013, pg. 189]} The anxiety experienced within an anxiety disorder is more persistent than developmentally normative anxiety or fear (typically lasting more than six months).^{[APA, 2013, pg. 189]} It is down to clinical judgement whether the fear or anxiety is out of proportion, because individuals with anxiety disorders will usually overestimate the dangers of certain situations which cause them anxiety.^{[APA, 2013, pg. 189]}

Anxiety disorders are a common feature of psychotic disorders, and should not be diagnosed separately if the anxiety occurs during the course of the psychotic condition.^{[APA, 2013, pg. 225]}

Panic disorder refers to a condition whereby an individual suffers from unexpected attacks of panic symptoms, including: palpitations, sweating, trembling, shortness of breath, choking feelings, chest pain or discomfort, nausea, dizziness, chills, numbness or tingling, derealisation or depersonalisation, fear of losing control, or fear of dying.^{[APA, 2013, pg. 209]} The severity and frequency of the attacks can vary from person to person, from daily to monthly.^{[APA, 2013, pg. 209]} Panic attacks are known to co-occur with other psychiatric conditions, including psychotic disorders and, when they do, they are associated with increased symptom severity and poorer treatment response.^{[APA, 2013, pg. 217]} In order to differentiate the diagnosis, the cause of the panic attacks must be considered; for a diagnosis of panic disorder, the panic attacks must be unexpected, if the attacks become associated with another disorder then they are no longer unexpected.^{[APA, 2013, pg. 213]}

Obsessive–compulsive disorder (OCD) is associated with reduced quality of life, and functional impairments.^{[APA, 2013, pg. 240]} It is defined as:^{[APA, 2013, pg. 237]}

• obsession; recurrent and persistent thoughts, urges, or images, that are experienced as unwanted or intrusive and that in most individuals cause anxiety or distress, which the individual attempts to suppress or neutralise with some other thought or action (e.g., a compulsion)
• compulsion; repetitive behaviour that the individual feels driven to perform in response to an obsession, and which is aimed at reducing anxiety or distress, but is not connected in a realistic way with what they are designed to neutralise, or are clearly excessive.

It is easy to see how the criteria for OCD, as described above, can overlap with those of schizophrenia.^{[APA, 2013, pg. 241]} Indeed, some individuals with OCD have poor insight into their own condition, and the obsessions of OCD can be delusional in nature.^{[APA, 2013, pg. 241]} Differential diagnosis is based on the full symptom set of the two conditions – individuals with schizophrenia also experience hallucinations and/or formal thought disorder.^{[APA, 2013, pg. 241]}
 

Substance-use disorders are a group of cognitive, behavioural, and physiological symptoms indicating that the individual continues to use a substance despite problems related to the use of that substance.^{[APA, 2013, pg. 483]} Substances can include alcohol, cannabis, hallucinogens, opioids, sedatives, and tobacco.^{[APA, 2013, pg. 482]} Substance-use disorders are typified by craving of a substance, tolerance, withdrawal symptoms, and continued use of a substance despite negative consequences, amongst other criteria.^{[APA, 2013, pg. 509]} 
Differentiating schizophrenia from the psychosis that can be experienced as a result of substance use focusses on the timeframe of the psychotic symptoms.^{[APA, 2013]} In schizophrenia, the psychotic symptoms are persistent and not attributable to the effects of a substance.^{[APA, 2013, pg. 105]}
 

Although smoking may alleviate some of the symptoms of schizophrenia, cigarette smoking is a modifiable risk factor for a whole host of physical conditions, including cardiovascular disease, and cancer.^{[APA, 2013, pg. 574; De Hert et al., 2011]}

Cannabis-use disorder is characterised by a patient exhibiting a problematic pattern of cannabis use that leads to clinically significant impairment, or to distress.^{[APA, 2013]} Cannabis use is often reported to be a form of self-medication, in order to cope with mood disorders, or other psychological problems.^{[APA, 2013]}
 

Comorbid substance use represents a barrier to carrying out effective treatment for schizophrenia, and is associated with its own set of health problems.^{[Winklbaur et al., 2006]} As well as reducing the likelihood of good treatment outcomes, comorbid substance use in patients with schizophrenia increases the chances of incarceration.^{[Winklbaur et al., 2006]} Integrated treatment models that account for psychotic symptoms and substance use have promise, but more research is needed to establish the optimal psychological and pharmacological therapies for this subgroup of patients.^{[Winklbaur et al., 2006]}

Coronary heart disease (CHD) is the main cause of excess premature mortality in patients with schizophrenia; the mortality rate from coronary heart disease in patients with schizophrenia is 50–75%, compared with 33% in the general population.^{[Hennekens et al., 2005]} Patients with schizophrenia are known to have enhanced risk of developing several conditions or comorbidities that increase the risk of heart disease, including smoking, dyslipidaemia, diabetes, obesity, and metabolic syndrome.^{[Correll, 2007; De Hert et al., 2009; Hennekens et al., 2005; Sadock et al., 2009]} 

This was a retrospective analysis of hospital data from the Premier Perspective Database® between April 2010 and June 2012.^{[Correll et al., 2017]} The study aimed to determine the prevalence of cardiometabolic comorbidities among hospital inpatients with schizophrenia and bipolar disorder and to assess the role of incremental cardiometabolic comorbidity burden on length of stay, mortality, and healthcare costs during the initial admission.^{[Correll et al., 2017]} The cardiometabolic comorbidities that were screened for included: cerebrovascular disease, coronary or ischaemic heart disease, diabetes mellitus, hyperglycaemia, hyperlipidaemia, and hypertension.^{[Correll et al., 2017]} After the 118,065 potential patients with schizophrenia were screened according to exclusion criteria, a total of 57,506 patients were included in the analysis.^{[Correll et al., 2017]}

The outcomes analysed were the length of stay in hospital, the readmission rate, and the mortality rate, stratified based on whether the patient had 0, 1, 2, or 3 or more cardiac comorbidities.^{[Correll et al., 2017]} As shown on the graph, the hospital readmission rate increased as the number of cardiac comorbidities increased, as did the mortality rate (the latter seeming to peak at 2 or more comorbidities).^{[Correll et al., 2017]} In terms of total costs, each incremental cardiometabolic comorbidity was associated with an 8.3% increase in costs (not shown on slide).^{[Correll et al., 2017]} These results demonstrate the added burden that cardiovascular/cardiometabolic comorbidites place on patients with schizophrenia, and reinforce the need for improved detection and management of cardiovascular health in this population.^{[Correll et al., 2017]}

Given the increased risk of metabolic syndrome in patients with schizophrenia, it is crucial that the treating psychiatrist is mindful of the potential metabolic adverse effects of any medications administered.^{[Mitchell et al., 2013]} Future research should be focussed on the possible genetic characteristics that determine susceptibility to metabolic syndrome, and whether cardiometabolic outcomes are mediated by any specific clinical features of the patient.^{[Mitchell et al., 2013]}

The greater incidence of dyslipidaemia in patients with schizophrenia has been well documented.^{[Correll, 2007; Hsu et al., 2012; Solberg et al., 2016]} There is ongoing debate regarding whether lipid disturbance in schizophrenia is a component of the disease or a result of antipsychotic therapy, and to what extent these two factors contribute to the lipid profile seen in patients with schizophrenia.^{[Hsu et al., 2012; Correll, 2007]}

Individuals with schizophrenia are at greater risk than the general population of developing diabetes, or glucose intolerance.^{[Correll, 2007; Subramaniam et al., 2003]} The association between schizophrenia and diabetes is thought to be partially explained by genetic factors.^{[Bushe & Holt, 2004]} However, it is also the case that patients with schizophrenia may display poor health behaviours, including having a poor diet and smoking, which are factors that may increase the risk of diabetes.^{[Bushe & Holt, 2004]} The strength of the association is such that patients with schizophrenia should be monitored for the risk factors of diabetes, allowing for early detection, and education of patients about the importance of a healthy lifestyle.^{[Bushe & Holt, 2004]}

Unravelling the relationship between schizophrenia and lung cancer involves tackling the key confounding variable of smoking.^{[Bushe & Hodgson, 2010]} When attempts have been made to control for the levels of smoking observed among patients with schizophrenia, there appears to be a slightly reduced risk of lung cancer in this population.^{[Bushe & Hodgson, 2010]} 

Other types of cancer are no less complicated, for example, as well as smoking, elevated glucose levels have been linked to some types of cancer, and schizophrenia has been shown to be a risk factor for diabetes.^{[Bushe & Hodgson, 2010; Correll, 2007]} Investigating these cancers in patients with schizophrenia involves attempting to control for the confounding factor of impaired glucose tolerance.^{[Bushe & Hodgson, 2010]} Moreover, there are likely to be risk variables that are simply not known, and so cannot be controlled in a study or a meta-analysis.^{[Bushe & Hodgson, 2010]}

It is clear that patients with schizophrenia have a higher risk of developing certain cancers, but it is not yet clear what this means.^{[Goldacre et al., 2005; Bushe & Hodgson, 2010]}
 

The higher incidence of smoking in patients with schizophrenia has to be taken into account when discussing COPD in schizophrenia, because smoking is a risk factor for the development of COPD.^{[Hsu et al., 2013]} In one study, a database sample of >700,000 individuals was screened to determine the incidence of COPD in patients with schizophrenia compared with the general population.^{[Hsu et al., 2013]} Schizophrenia was associated with an elevated risk of COPD, with an odds ratio of 1.66 (95% confidence interval [CI]: 1.42–1.94).^{[Hsu et al., 2013]} However, the highest odds ratio was found in the youngest group, aged 18–29, wherein the odds ratio was 3.50 (95% CI: 2.23–5.48).^{[Hsu et al., 2013]}
 

This study used a database sample of >600,000 individuals to determine the incidence of liver diseases in patients with schizophrenia compared with the general population.^{[Hsu et al., 2014]} For the purposes of the study, chronic liver disease included: alcoholic fatty liver, acute alcoholic hepatitis, alcoholic cirrhosis of the liver, alcoholic liver damage, unspecified, chronic hepatitis, cirrhosis of the liver without mention of alcohol, biliary cirrhosis, other chronic non-alcoholic liver disease, and unspecified chronic liver disease without mention of alcohol.^{[Hsu et al., 2014]} An odds ratio of 1.27 was found, indicating that patients with schizophrenia have a heightened risk of liver diseases, however, in patients aged 18–29 the odds ratio was 1.90.^{[Hsu et al., 2014]} A consistent theme, when discussing the comorbidities of schizophrenia, these results highlight the importance of detection of liver diseases in patients with schizophrenia, so that treatment can be given as early as possible.^{[Hsu et al., 2014]} 

The comorbidities associated with schizophrenia may have an impact on the quality of life of the patient,^{[APA, 2013; Carrà et al., 2016; Hou et al., 2016]} however, there are indications that some specific comorbidities may be linked to better long-term outcomes,^{[Sim et al., 2006]} or reduced negative symptoms.^{[Carrà et al., 2016]}

Ultimately, patients with schizophrenia face a greater medical burden than the general population, and schizophrenia is a condition that is associated with a significant occupational and social dysfunction on its own.^{[APA, 2013, pg. 104]} The condition is also associated with an elevated risk of suicide, with approximately 5–6% of patients with schizophrenia dying by suicide.^{[APA, 2013, pg. 104]} The added burden of the comorbid medical conditions that are associated with schizophrenia further reduce the life expectancy of patients with this debilitating condition.^{[APA, 2013, pg. 105]}

The slide summarises some of the barriers that exist that prevent the recognition and management of physical diseases in patients with severe mental illness, including schizophrenia.^{[De Hert et al., 2011a; De Hert et al., 2011b]} 

Treatment guidelines for schizophrenia recognise the high rates of somatic comorbidities in patients with schizophrenia, and recommend taking the patient’s medical history and general medical status into account when considering treatment options.^{[Falkai et al., 2005]} Particularly, when considering antipsychotic treatments, the potential adverse effects should be considered; for example, a treatment with effects on QTc interval should not be prescribed to a patient with existing heart problems.^{[Falkai et al., 2005]} One of the challenges of treating physical illnesses in patients with severe mental illness is that often the only contact they will have with a medical team will be with psychiatric services.^{[De Hert et al., 2011b]} Although it places a burden on mental health services, it is increasingly being recognised that patients with schizophrenia should be monitored for physical health problems,^{[De Hert et al., 2011b]} as well as the modifiable health risk factors that are largely to blame for the excess mortality in patients with severe mental illness.^{[De Hert et al., 2011a]}