SCHIZOPHRENIA COMORBIDITIES AND PATHOPHYSIOLOGY

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Common physical comorbidities and behavioral risk factors in schizophrenia

Dysregulation of neural systems in schizophrenia has been hypothesized to result in behavioral risk factors that may contribute to a range of comorbidities.1

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Substance use

Dysregulation of the mesocorticolimbic dopamine reward circuit is hypothesized to contribute to the vulnerability of patients with schizophrenia to the initiation and continued use of substances. More research is needed to understand the co-occurrence of schizophrenia and substance use disorder.2

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Infectious disease

Studies have reported greater odds or risk of infectious diseases in patients with schizophrenia with co-occurring substance use disorder. In a 2006 review of records from the Veterans Integrated Service Network, patients with schizophrenia and co-occurring substance use disorder had ≈8x greater odds of hepatitis C infection compared with controls.3 In a 2015 review of nationwide records in Denmark, patients with schizophrenia and co-occurring substance use disorder had ≈1.8x greater risk of HIV infection compared with the general population.4

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Tobacco use

In a 2012 meta-analysis, patients with first-episode psychosis, including those with schizophrenia, were 6 times as likely to use tobacco compared with age- and gender-matched controls. This analysis was consistent with another systematic review of 42 studies from 20 nations in which patients with schizophrenia were 6 times as likely to use tobacco as the general population.5 In a separate 2014 study, smokers with schizophrenia or schizoaffective disorder (n=28) had greater cigarette cravings in anticipation of relief of negative affect than controls without psychiatric illness (n=27) during abstinence. There are many hypotheses for the higher prevalence of smoking in patients with schizophrenia, including theories of increased negative symptomatology, deficits in reward processing, and alterations in reward-related brain circuitry.6,7

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Respiratory disease

A 2004 survey study reported greater odds of respiratory diseases in patients with schizophrenia or schizoaffective disorder (n=100) compared with the general population. Patients with schizophrenia were observed to have 2.4, 3.7, and 9.1 times the odds of asthma, chronic bronchitis, and emphysema, respectively, compared with the general population. When controlled for smoking, the odds for asthma, chronic bronchitis, and emphysema were approximately 2.2, 3.1, and 7.2 times greater, respectively.8

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Altered reward anticipation and dysregulated energy allocation

The current understanding of the neuroscientific basis of weight gain in schizophrenia is limited. One hypothesis is altered reward anticipation, which is hypothesized to be related to striatal dopaminergic dysregulation. Decreased striatal dopamine signaling may be associated with reduced sensitivity to natural rewards and lead to compensatory, compulsive eating in both obesity and schizophrenia. Low dopamine levels associated with schizophrenia may also result in dysregulated energy allocation. However, this content is theoretical and more research is needed to confirm this hypothesis.9

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Cardiovascular disease

In 2009, the European Psychiatry Association (EPA) suggested several potential reasons for increased cardiovascular disease (CVD) among patients with SMI, including schizophrenia.10

  • Increased likelihood of metabolic risk factors, including diabetes, hypertension, dyslipidemia, and obesity
  • Unhealthy lifestyle, including poor diet and sedentary behavior, and increased likelihood of smoking
  • Less access to healthcare and cardiovascular risk screening and prevention for many patients

Pathophysiology of schizophrenia may involve dysfunction across several neurotransmitter systems

Historically, core symptoms of schizophrenia have been attributed to dysregulation of the dopaminergic system, but others have also been implicated. Neurotransmitters proposed to play a role in schizophrenia pathophysiology include, but are not limited to, dopamine, glutamate, serotonin, acetylcholine, and γ-amino-butyric acid (GABA).11-13

Two prominent hypotheses of schizophrenia pathophysiology are the revised dopamine hypothesis and the N-methyl-d-aspartate (NMDA) hypothesis.

Dopamine hypothesis of schizophrenia11,12

Dopamine hyperactivity
in the mesolimbic
regions of the brain
Dopamine
hypoactivity in
the prefrontal cortex
Symptoms of
schizophrenia

NMDA hypothesis of schizophrenia13,14

Dysregulated glutamatergic
neurotransmission
Negative symptoms
& cognitive impairment

Schizophrenia may involve dysfunction across several systems

In addition to dysfunction of the central nervous system (CNS), schizophrenia may involve cardiometabolic disturbance, immune system disturbance, and endocrine disturbances. This was observed in a systematic meta-review from 165 case-control studies, including 6 studies of first-episode, antipsychotic-naive patients with schizophrenia.15

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Metabolic
disturbance

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Endocrine
disturbance

Icon consisting of cellular components of the immune system

Immune
disturbance

Dysregulation across these systems has been observed in several additional studies of patients with schizophrenia:

Reduced adiponectin levels have been observed in patients with schizophrenia.16

  • 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 2017.16-18 Several studies have shown an association between low serum adiponectin levels and insulin resistance, type 2 diabetes, and cardiovascular disease in humans19
  • The association between adiponectin and antipsychotic-naive schizophrenia is still unclear. Lower serum adiponectin levels have been detected in this subpopulation compared with healthy controls16,20
  • Lower adiponectin levels have also been observed in antipsychotic-prescribed patients with schizophrenia16,20

Elevated blood cytokine levels have been observed in antipsychotic-naive first-episode patients with schizophrenia, according to a 2018 systematic meta-review from 165 case-control studies, including 4 studies that examined immune profile in antipsychotic-naive patients.15

  • 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 psychosis15
  • Adipose tissue also releases pro-inflammatory cytokines (IL-6 and TNF-α), which may contribute to insulin resistance,21 and antipsychotic-naive patients with schizophrenia who have higher BMI have been observed to have increased levels of C-reactive protein, a biomarker of inflammation directly modulated by IL-622

A 2016 meta-analysis of 208 antipsychotic-naive patients, including patients with schizophrenia, reported elevated prolactin levels in male and female patients compared with matched controls.23

  • Prolactin is a polypeptide hormone secreted from the anterior pituitary gland. It is believed that prolonged elevations in prolactin may be associated with certain health effects, including amenorrhea, galactorrhea, osteoporosis, low libido, erectile dysfunction, and breast cancer, as reported in a 2016 study23
  • Prolactin release may be increased in response to stress and be associated with HPA activity15,23

 

BMI=body mass index; IL-6=interleukin six; TNF-α=tumor necrosis factor alpha.

Opportunities
to Manage the
WHOLE PATIENT

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BIPOLAR DISORDER BIPOLAR DISORDER
Comorbidities and
Pathophysiology

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References: 1. 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. 2. Khokhar JY, Dwiel LL, Henricks AM, Doucette WT, Green AI. The link between schizophrenia and substance use disorder: a unifying hypothesis. Schizophr Res. 2018;194:78-85. 3. Huckans MS, Blackwell AD, Harms TA, Hauser P. Management of hepatitis C disease among VA patients with schizophrenia and substance use disorders. Psychiatr Serv. 2006;57(3):403-406. 4. Helleberg M, Pedersen MG, Pedersen CB, Mortensen PB, Obel N. Associations between HIV and schizophrenia and their effect on HIV treatment outcomes: a nationwide population-based cohort study in Denmark. Lancet HIV. 2015;2(8):e344-350. 5. Myles N, Newall HD, Curtis J, Nielssen O, Shiers D, Large M. Tobacco use before, at, and after first-episode psychosis: a systematic metaanalysis. J Clin Psychiatry. 2012;73(4):468-475. 6. Tidey JW, Colby SM, Xavier EM. Effects of smoking abstinence on cigarette craving, nicotine withdrawal, and nicotine reinforcement in smokers with and without schizophrenia. Nicotine Tob Res. 2014;16(3):326-334. 7. Lucatch AM, Lowe DJE, Clark RC, Kozak K, George TP. Neurobiological determinants of tobacco smoking in schizophrenia. Front Psychiatry. 2018;9:672. 8. Sokal J, Messias E, Dickerson FB, et al. Comorbidity of medical illnesses among adults with serious mental illness who are receiving community psychiatric services. J Nerv Ment Dis. 2004;192(6):421-427. 9. Grimm O, Kaiser S, Plichta MM, Tobler PN. Altered reward anticipation: potential explanation for weight gain in schizophrenia? Neurosci Biobehav Rev. 2017;75:91-103. 10. De Hert M, Dekker JM, Wood D, Kahl KG, Holt RI, Moller HJ. Cardiovascular disease and diabetes in people with severe mental illness position statement from the European Psychiatric Association (EPA), supported by the European Association for the Study of Diabetes (EASD) and the European Society of Cardiology (ESC). Eur Psychiatry. 2009;24(6):412-424. 11. Brisch R, Saniotis A, Wolf R, et al. The role of dopamine in schizophrenia from a neurobiological and evolutionary perspective: old fashioned, but still in vogue. Front Psychiatry. 2014;5:47. 12. Toda M, Abi-Dargham A. Dopamine hypothesis of schizophrenia: making sense of it all. Curr Psychiatry Rep. 2007;9(4):329-336. 13. Yang AC, Tsai SJ. New targets for schizophrenia treatment beyond the dopamine hypothesis. Int J Mol Sci. 2017;18(8):1689. 14. Balu DT. The NMDA receptor and schizophrenia: from pathophysiology to treatment. Adv Pharmacol. 2016;76:351-382. 15. Pillinger T, D'Ambrosio E, McCutcheon R, Howes OD. Is psychosis a multisystem disorder? A meta-review of central nervous system, immune, cardiometabolic, and endocrine alterations in first-episode psychosis and perspective on potential models. Mol Psychiatry. 2019;24(6):776-794. 16. Freyberg Z, Aslanoglou D, Shah R, Ballon JS. Intrinsic and antipsychotic drug-induced metabolic dysfunction in schizophrenia. Front Neurosci. 2017;11:432. 17. Diez JJ, Iglesias P. The role of the novel adipocyte-derived hormone adiponectin in human disease. Eur J Endocrinol. 2003;148(3):293-300. 18. Di Chiara T, Argano C, Corrao S, Scaglione R, Licata G. Hypoadiponectinemia: A link between visceral obesity and metabolic syndrome. J Nutr Metab. 2012;2012:175245. 19. Menzaghi C, Trischitta V, Doria A. Genetic influences of adiponectin on insulin resistance, type 2 diabetes, and cardiovascular disease. Diabetes. 2007;56(5):1198-1209. 20. Cohn TA, Remington G, Zipursky RB, Azad A, Connolly P, Wolever TM. Insulin resistance and adiponectin levels in drug-free patients with schizophrenia: a preliminary report. Can J Psychiatry. 2006;51(6):382-386. 21. Leonard BE, Schwarz M, Myint AM. The metabolic syndrome in schizophrenia: is inflammation a contributing cause? J Psychopharmacol. 2012;26(5 Suppl):33-41. 22. Fernandes BS, Steiner J, Bernstein HG, et al. C-reactive protein is increased in schizophrenia but is not altered by antipsychotics: meta-analysis and implications. Mol Psychiatry. 2016;21(4):554-564. 23. Gonzalez-Blanco L, Greenhalgh AMD, Garcia-Rizo C, Fernandez-Egea E, Miller BJ, Kirkpatrick B. Prolactin concentrations in antipsychotic-naive patients with schizophrenia and related disorders: a meta-analysis. Schizophr Res. 2016;174(1-3):156-160.