The Common Pathophysiology Underlying the Metabolic Syndrome, Schizophrenia and Depression. a Review

Background. There is a growing interest in metabolic alterations in patients with psychiatric disorders due to their increased risk for metabolic syndrome (MetS) development. Inflammation is known to underlie the pathophysiology of schizophrenia and depression as well as MetS. Vulnerability factors for schizophrenia/depression and MetS hence appear to be shared. Methods and Results. Based on a Web of Science search, this review examines current evidence for MetS pathophysiol-ogy involving dysregulation of adipose tissue signaling – adipokines and pro-inflammatory cytokine, both also known to be aberrant in schizophrenia/depression. Further, gender differences in the incidence and course of schizophrenia/ depression were reported. The disturbances linked to the MetS are also described. Therefore, this review further maps the gender differences in the psychiatric-metabolic comorbidities. Conclusion. There is evidence supporting a pathological predisposition to MetS in both schizophrenia and depression in both humans and animal models. This predisposition is dramatically enhanced by antipsychotic medication. Further, there are gender differences from clinical findings suggesting women with schizophrenia/depression are more vulnerable to MetS development. This has not yet been assessed in animal studies. We suggest further validation of existing schizophrenia and depression animal models for the assessment of metabolic disturbances to provide tools for developing new antipsychotics and antidepressants with " metabolically inert " profile or improving the metabolic status in schizophrenic/depressed patients.


INTRODUCTION
Psychiatric disorders are commonly associated with increased morbidity and mortality largely due to other medical conditions such as cardiovascular diseases, diabetes, respiratory and infectious diseases.There is a rapidly growing interest in the assessment of metabolic disturbances in patients diagnosed with psychiatric disorders (especially schizophrenia and depression) due to their higher risk of metabolic syndrome (MetS) than the general population.In addition, growing evidence indicates a role of inflammation in the pathophysiology of these diseases.
In the US and European populations, the prevalence of MetS in psychiatric patients ranges from 25-56% (depending on definition) and it constitutes major health and financial burdens [1][2][3] .It is estimated to be up to 50% higher than age-matched healthy control populations 4 with expectation to rise to 59% by 2020 (ref. 5).Moreover, not only western populations are affected but also eastern regions report a high prevalence.More particularly, Asian populations report a mean prevalence of 20-40% (ref. 6), South American regions with 14-30% and Australia with 20-30% (ref. 1 ).Further, younger age groups also show a growing rate of MetS incidence 7 .A number of reports confirm the psychiatric populations have a substantially higher incidence of MetS than the general population, especially in the case of schizophrenia 8 and depression 9 .
Obesity and MetS development are also known to differ according to gender as a result of differences in the amount and distribution of body fat and differences in adipose tissue metabolism and function between the sexes 10 .The incidence of MetS was reported to be higher in women than in men in Arabic populations 11 , a finding consistent with European populations 12 .Therefore, a gender-specific approach may be more effective for the treatment and prevention of MetS development.
The need for reviewing current knowledge on the shared pathophysiology linking MetS and psychiatric disorders is supported by increasing numbers of publications on the topic of comorbid MetS and schizophrenia/ depression.Web of Science search (performed in August 2014) for "metabolic syndrome" and "schizophrenia*" in publication titles currently provides 186 records, with the oldest from the year 2002 including 11 reviews.However, most papers (and reviews) focus on the side-effects of anti-psychotics and not the pathophysiological causes according to the disorders per se resulting in MetS.Analogous search for depression ("depress*") returns 161 publications with the oldest from the 2003 including 5 review papers.
The aim of this review was to evaluate the available findings on the link between MetS and schizophrenia/ depression with a focus on gender differences.

METABOLIC SYNDROME AND INFLAMMATION
The epidemic spread of MetS has resulted in over 2 billion overweight and obese adults worldwide 13 .This syndrome is defined as a complex of risk factors closely related to the development of atherosclerosis and subsequent cardiovascular morbidity together with type-2 diabetes.In particular, these factors comprise mainly abdominal distribution of adipose tissue (abdominal obesity), dyslipidemia, hypertension and distortion of glycemic homeostasis 14 .The seriousness of this pathology lies in increased mortality due to cardiovascular conditions and diabetes type 2. Compared to normal populations, the incidence of myocardial infarction and stroke are 3-fold higher in MetS patients; the risk of type 2 diabetes development is 5-fold higher 15 .Individuals with MetS also often manifest pro-thrombotic and pro-inflammatory states reflected by higher blood levels of pro-inflammatory cytokines such as interleukin-6 (IL-6), interleukin-12 (IL-12), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interferon-γ (ref. 16).
Dysregulation of adipokines as biomarkers of adipose tissue metabolism plays an essential part in all obesityrelated diseases.Most relevant adipokines known to be dysregulated in MetS are leptin, adiponectin (both supporting insulin signaling functions), resistin and adipocyte fatty acid binding protein (AFABP).Also pro-inflammatory cytokines are considered adipokines such as interleukins, TNF-α and C-reactive protein (CRP), all generally suppressing insulin signaling functions.
Leptin is a peripheral signaling protein that regulates the hypothalamic satiety center and adipose reserves in the body 17,18 .It is key mediator of energy homeostasis involving regulation of appetite, lipid catabolism and inhibition neurotransmitter neuropeptide Y, a known appetite stimulator 19 .Plasma levels of leptin are generally higher in obese patients, which is considered to be a leptin-tolerant state 20,21 .
Adiponectin is a protein that inhibits inflammatory reactions and protects against metabolic disease, by a wide range of mechanisms, including anti-diabetic, anti-inflammatory and anti-sclerotic 22 .It is involved in the regulation of carbohydrate and lipid metabolism, inhibiting gluconeogenesis in liver and increasing the transport and utilization of free fatty acids in the periphery.Furthermore, it significantly affects the function of insulin and plays an important role in energy homeostasis, causing a decrease in body weight without affecting food intake.However, it is believed that it also directly influences the regulation of appetite and weight control 21,23 .
Resistin is a peptide hormone produced by mature adipocytes and regulates insulin sensitivity 24 .Its inhibitory effect on the differentiation of adipocytes probably underlies its role in the feedback between nutritional status and adipogenesis.Its plasma levels increase in correlation with inflammatory markers including CRP, soluble TNF-α receptor-2, IL-6 and lipoproteins in combination with phospholipase A2 under pathophysiological conditions related to inflammation 25 .Based on preclinical evidence, resistin may represent a key link between inflammation and its metabolic consequences 21,[26][27][28] .
AFABP is a newly discovered adipokine found at higher plasma levels in patients who have the MetS.Patients with higher levels of AFABP have worse prognosis and increased cardio-metabolic risk factors, reversible by atorvastatin treatment 29 .Further, TNF-α is constitutively expressed in adipose tissue and this condition leads to insulin resistance in animal models of obesity which supports the face validity of the models.Plasma levels of AFABP in humans closely correlates with degree of obesity and the development of insulin resistance and positively correlates with waist circumference, blood pressure values, and parameters of lipid metabolism, serum fasting insulin and insulin resistance index 21,30 .
2][33] ) and MetS is also associated with other inflammatory diseases such as rheumatoid arthritis 34 showing secondary development of MetS on an inflammatory basis.The hypothesis assumes obesity is a consequence of excessive caloric intake representing a sub-clinical inflammatory process, which induces insulin resistance and following clinical and biochemical manifestations of MetS as demonstrated in numerous studies.For review see Alemany et al. 31 Moreover, the inflammation is mediated by pro-inflammatory cytokines produced by macrophages which tend to populate the growing adipose tissue in obesity at higher rates 35 .In mouse obesity models, an up-regulation of specific genes for macrophages -macrophage inflammatory protein 1α (MIP-1α), monocyte chemoattractant protein-1 (MCP-1), macrophage-1 antigen (MAC-1), macrophage surface glycoproteins F4/80 and CD68; and genes promoting inflammatory processes in white adipose tissue are found.Molecular mechanisms leading to macrophage activation in obesity/ MetS are not fully understood.However, participation of adipokines (adiponectin, leptin, complement factor C3, MCP-1, cytokines, free fatty acids) is assumed 36 .Activated macrophages release several cytokines and chemokines such as TNF-α (ref. 37), IL-1, IL-6 and MCP-1, distorting adipocyte sensitivity to insulin, which then in turn promote further activation and infiltration of macrophages.Therefore, impaired insulin signaling in adipocytes may lead to massive lipolysis, necrosis and development of insulin resistance 33,38 .

PSYCHIATRIC DISORDERS AND INFLAMMATION
There is accumulating evidence suggesting that schizophrenia is associated with increased serum levels of proinflammatory cytokines, namely IL-1, IL-6, TNF-α and high-sensitivity CRP, even in patients with minimal or no exposure to antipsychotics 39 .
Prenatal infections are also hypothesized to have serious impact on the brain, which is supported by validation of several neurodevelopmental animal models of schizophrenia based on immune or toxic prenatal insult namely: Immune: polyIC (polyriboinosinic-polyribocytidilic acid) model 40 , toxic: MAM (methylazoxymethanol acetate) model 41 or Δ9-THC (Δ9-tetrahydrocannabinol) model 42 .Together with certain genetic factors, these findings provide convincing evidence that inflammation is a major factor in the pathology of this disorder 43 .
There is a well-established concept of depression strongly associated with inflammation.An abundance of both clinical and preclinical data reported increases in pro-inflammatory cytokines such as IL-1, IL-6, TNF-α and CRP in depressed patients [44][45][46][47] .Similar findings were also discovered in preclinical studies 48 including the olfactory bulbectomized rodent model of depression 49 .

Schizophrenia and metabolic syndrome
Obesity or MetS are common in schizophrenic patients.MetS has an incidence of 3-4% in the general population, but up to 10% in schizophrenic patients even before initiation of the treatment with antipsychotics 8 which often results in typical changes in lipid metabolism 50 .It appears that not only antipsychotic treatment but the pathophysiology of schizophrenia itself is linked to MetS development suggesting a common underlying pathway-chronic inflammatory abnormality of cytokines 43 .Therefore, vulnerability factors for development of schizophrenia, diabetes, and MetS seem to be shared and interconnected.In patients with schizophrenia the risk is further greatly increased by the use of antipsychotic medication as reviewed repeatedly elsewhere 8,[51][52][53][54][55] .
More specifically, elevated blood levels of adiponectin have been reported in schizophrenia 56 and there is a correlation between serum leptin levels and body weight 51 .In addition, leptin concentration was shown to play an important part in the negative feedback against dopamine activity connected to positive symptoms of schizophrenia 57 .Furthermore, it is well known that antipsychotic treatment induces clinically relevant weight gain and rise in fasting plasma glucose levels 58 .
Despite the high clinical relevance, relatively little research has been done in preclinical models of schizophrenia, which could then contribute to targeted drug development for MetS treatment in psychotic patients.Studies conducted in animals were mostly related to the evaluation of metabolic effects in all classes of antipsy-chotics rather than the assessment of the relation between MetS and schizophrenic phenotype per se.These drugs were shown to notably disturb lipid metabolism in drug naïve Sprague-Dawley rats as well as in kainic acid treated Fisher rats used as a model of schizophrenia 59,60 .This indicates that schizophrenic-like phenotype in rodent models and antipsychotic medication does lead to increase in vulnerability to metabolic disturbances further confirming their validity and translational potential evaluating gender differences, a key importance for developing new therapeutic strategies as described in the corresponding section of this text.

DEPRESSION AND METABOLIC SYNDROME
Multiple lines of evidence confirm higher incidence of MetS in depressed patients.A 50% higher prevalence of depression has been reported in individuals with MetS in an Australian population 61 and a 4-fold increased risk for MetS in patients with lifetime major depression episode in a Lithuanian population 62 .Similar outcomes in a German population were found 63 .Also, different ethnic groups were compared with consistent finding of higher MetS prevalence in depressed African-American, Caucasian 64 , and Asian women 65 .Furthermore, not only major depression but also bipolar disorder has been shown to have association with MetS (ref. 66).However, MetS seems to be specifically linked to depression as it has been repeatedly shown that anxiety is not associated with metabolic disturbances 62,67 .
There are also clinical studies showing no 68 or only partial association of MetS symptoms (lipid profile) with depression 69 .However, recently, Pan et al. published an extensive meta-analysis (the first of its kind) reporting a strong link between depressive disorders and development of MetS in both genders.The results indicate a convincing bidirectional association between depression and MetS (ref. 9).Further support (although sporadic) for the association between MetS and depression could provide a case study of a (Caucasian) woman treated with pioglitazone and showing strong antidepressant effect 70 .
Suggested mechanisms underlying both disorders include HPA axis dysregulation following the inflammatory reaction.Moreover, two subtypes of depression (melancholic and atypical depression) were identified to be associated with the inflammatory and metabolic dysregulation.This highlights the possibility that not all forms of major depression possess this association with MetS (ref. 71).Changes in important adipokine levels in depressed patients were reported compared to a healthy population suggesting predisposition to MetS development in depressed patients.In agreement, a "leptin hypothesis of depression" was formulated as low levels of leptin have been found in association with depression in humans as well as depressive behaviors in rodents.It was suggested that both leptin insufficiency and leptin resistance may contribute depressive status 72 .These findings are translated and further supported by several animal studies 73 including pharmacological experiments where leptin induced antidepressive-like behaviour in a forced swimming test, a commonly used test for evaluation of depressive-like phenotype in rodents 74 .
Blood levels of another adipokine -adiponectin -were found to be reduced in Brazilian patients with major depression before antidepressant treatment.The authors of the study (Leo et al. 2006) conclude that the reduced availability of circulating adiponectin is likely to have an impact on mood state 75 .Similar findings were reported in an Italian population 76 and later in a US population 77 .However, contradictory findings were reported in a Korean study showing higher levels of adiponectin in depressed individuals 78 .The variability could be due to antidepressant treatment which seems to increase adiponectin levels 79 .Yet, studies reporting no difference before and after treatment have also been published 80 .
Regarding resistin, a positive association between blood levels and free cortisol concentrations were found in depressed patients.Resistin levels were normalized when patients remitted after pharmacological treatment but not in non-remitters 80 .

Schizophrenia and MetS: implications of gender
Sex-specific differences in the epidemiology, onset and course of schizophrenia are repeatedly reported.More specifically, men have approximately 4-times higher tendency to develop schizophrenia and the first symptoms usually appear at a younger age 81 .On the other hand, women tend to suffer more from comorbid depression while men it is drug addiction.In addition, gender differences in response to antipsychotic treatment are reported.However, a clear explanation is yet to be provided.Influences of sex hormones, sexual dimorphism of the brain, metabolic differences and social factors were so far only proposed as partial explanations 82,83 .Gender differences in MetS comorbidity with schizophrenia were found repeatedly before and after the initiation of the antipsychotic treatment with women being approximately 3-times more prone to develop MetS (ref. 8).
Furthermore, preclinical studies have recorded gender differences suggesting a greater vulnerability (increase in body weight and metabolic changes) in female rats, specifically, the most suitable model for antipsychoticinduced weight gain appears to be the female Sprague-Dawley rat 84 .In contrast, male rats showed no significant changes in body mass yet still exhibited metabolic disturbances such as increased visceral fat mass and hormonal changes 59 .Nevertheless, increased adiposity was reported in both genders and seems to be adequately modeled in rodents with a schizophrenic phenotype.It has not yet been established which experimental paradigms most accurately reflect weight gain and metabolic abnormalities in schizophrenia, known to be increased by antipsychotic treatment in humans 85 .

Depression and MetS: implications of gender
In the case of depression, reports of gender differences are only recently emerging.A similar strength of the overall association has been reported between metabolic risk factors in men and women, but in males, several factors were associated with depressive symptoms, while in females the association was confined to waist circumference only 86 .Earlier, a stronger association of MetS with depression was found in the female US population compared to male group 87 similarly in the Israeli population 88 .However, negative findings have been published as well 89 .Furthermore, depressed women showed significantly higher leptin levels than a control group both before and after the response to antidepressant treatment, whereas no difference was found between the male patients and their controls.The improvement of depression with antidepressant treatment was shown to cause a further elevation of leptin levels, in both female and male patients.Therefore, clinical response to antidepressant treatment seems to be linked to leptin metabolism 90 .In addition, adiponectin levels were found to be dysregulated in men with depression while no differences were observed in that of women 78 .

CONCLUSION
In summary, there is likely a metabolic predisposition to MetS in both schizophrenia and depression patients which is evidence of underlying pathophysiology in both humans and animal models.This predisposition is enhanced by antipsychotic medication in psychotic patients.In agreement, numerous authors in clinical fields have already suggested screening for MetS in psychiatric patients to combat increased rates of morbidity and mortality from non-psychiatric reasons in these patients with early lifestyle and pharmacotherapeutic interventions.Specifically, in schizophrenic patients, routine consultation with a diabetologist has been suggested 52 .
Moreover, development of new anti-inflammatory treatments for the dual pathology of schizophrenia and MetS has been proposed 91 , which also could be a useful approach alleviating the cognitive symptoms of schizophrenia 92 .This evidence concerns newly diagnosed patients as well, with chronic treatment with antipsychotics being a well-known risk factor for MetS development.Thus, a follow-up monitoring of metabolic abnormalities in patients on second generation antipsychotics is strongly recommended by the consensus of the American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists, and North American Association for the Study of Obesity 93 .
In depression, a closer monitoring for MetS (ref. 61,63,94) together with development of disease-modifying therapies 95 and special regards to sex-differences 96 have been repeatedly suggested.Further, the current scientific literature has suggested the validation of existing animal models and the development of newer models to better reflect psychiatric diseases 97,98 .
Furthermore, the possible gender differences in clinical findings (suggesting women with schizophrenia/de-pression are more vulnerable to MetS development) are not yet assessed in animal studies.In the light of evidence on gender differences in MetS development in psychiatric disorders, sex differences should be taken into account in future preclinical and clinical studies.However, the lack of validated animal models for assessment of metabolic disorders comorbid in psychiatric diseases is problematic.Such validation of existing animal models of schizophrenia and depression could provide a useful tool for developing innovative pharmacotherapeutic solutions with "metabolically inert" profile or even improving the metabolic status of psychiatric patients.
The endocannabinoid system targeting drugs are an important source of candidates and have already been proposed for the treatment of schizophrenia 99,100 and mood disorders 101 .Endocannabinoid targeting drugs effective in reducing abdominal obesity have been identified 102 .More specifically, these drugs act through CB1 receptor inverse agonism.Unfortunately, marketing of the first drug, rimonabant, was discontinued for psychiatric sideeffects, namely inducing depressive states and suicidal ideas 103,104 .However, newer cannabinoid compounds are emerging and a strong influence on appetite, metabolism and energy homeostasis is consistently reported [105][106][107] .Most importantly, preclinical studies are constantly widening the range of new candidate molecules 108-110 .