Faculty of pharmacy department of human pharmacology and toxicology

UNIVERSITY OF VETERINARY AND PHARMACEUTICAL SCIENCES BRNO

FACULTY OF PHARMACY

DEPARTMENT OF HUMAN PHARMACOLOGY AND TOXICOLOGY



AUTHOR: Lazaropoulou Vasiliki

SUPERVISOR: PharmDr. Horska Katerina

DECLARATION
I declare that this thesis is my original copyrighted work. All literature and other resources I used while processing are listed in the bibliography and properly cited.

Author’s signature

ACKNOWLEDGEMENT

Special thanks to my supervisor

ABSTRACT

The aim of this review is the investigation of the relationship between metabolic abnormalities and psychiatric disorders analyzing the similarities in their biological pathways. Evidence shows that obesity and mood disorders share common molecular pathways.

Also, it has been suggested that antipsychotic medication causes significant weight gain through its effect on hormones such as leptin levels, the activation of TNF-αa system and cytokine receptors.

The present review is focused on the factors that contribute to the pathophysiology of obesity and mood disorders, their common pathways and the weight gain effect of antipsychotic medication, antidepressants, and mood stabilizers.

Keywords: mood disorders, obesity, BMI, schizophrenia, MDD, BP, leptin, cortisol, antipsychotics, antidepressants, mood stabilizers
ABSTRAKT

Cílem této přehledové práce je zkoumat vztah mezi metabolickými abnormalitami a psychiatrickými onemocněními nalézáním podobností v jejich biologických cestách. Existují důkazy, že obezita a duševní poruchy mají některé molekulární mechanismy společné.

Rovnež bylo navrženo, že antipsychotika způsobují významný váhový příbytek přes ovlivnění hormonů, jako je leptin, aktivací TNF-α a cytokinových receptorů.

Tato přehledová práce se zabývá faktory, které přispívají k patofyziologii obezity a duševních onemocnění, společnými cestami podmiňující tato onemocnění a účinkem antipsychotik, antidepresiv a stabilizátorů nálady na zvýšení hmotnosti.

Klíčová slova: antidepresiva, antipsychotika, BMI, duševní poruchy, kortizol, leptin, MDD, obezita, schizofrenie, stabilizátory nálady, TK.

Content

1. 
   Introduction
   
2. 
   Epidemiology
   
3. 
   Metabolic abnormalities involved in mental disorders
   

Dyslipidemia

Glucose disturbances

The role of kynurenine pathway…………………………………..

HPA axis

Adipose derived hormones

4. 
   Factors involved in the correlation between metabolic abnormalities and Mood Disorders
   

Genetic

Developmental aspects

Environmental

Brain substrates

5. 
   Drugs and how can cause metabolic abnormalities
   

Antipsychotics

Antidepressants

Mood stabilizer

6. 
   Discussion
   

References

1. Introduction

Evidence shows that mood disorders and obesity have an unbreakable relevance as they share genetic, neurobiological, clinical and environmental agents presenting co-morbidity. Various empirical studies have attempted to demonstrate the correlation between those health situations and more specifically have tried to describe the subtypes of mood disorders that develop obesity and metabolic problems. Despite the efforts, the knowledge about this correlation is limited, exceptions in the evaluation of mood and metabolic disorders exist.

Questions persist about the generalizability and validity of the findings in several studies evaluating metabolic-mood syndrome. The limitation factor is the heterogeneity, phenotypic and pathophysiological, of metabolic mood disorders. In the field of psychopathology there is an effort to categorize domains focused on pathogenic substrates, as suggested by the National Institute of Mental Health Research Domain Criteria Project. The existence of metabolic-mood syndrome is possible due to accumulating evidence showing an association of multiple abnormalities in neuropsychology and brain abnormalities concerning metabolic dysfunction. (Mansur, Brietzke & McIntyre, 2015).

Research data support an increased incidence of mood disorders in obese people, including major depression, dysthymia, manic and hypomanic episodes. The connection between mood disorders and obesity is stronger regarding women, while the relationship between higher BMI and alcohol abuse is more connected to men. Depression may be the result of obesity, but it might be related to its occurrence and development. The association between obesity and mood and anxiety disorders may be a result of stress on the hypothalamic-pituitary-adrenal axis (HPA), which reacts by releasing cortisol and other hormones that regulate sympathetic nervous system activity. In chronic stress, the HPA axis activity is deregulated and this deregulation classifies depressive and anxiety disorders and obesity (Collins & Bentz, 2009; Carr & Friedman, 2005).

Metabolic abnormalities related to weight gain have shown a linkage to various psychiatric disorders including bipolar disorder, major depressive symptoms, schizophrenia and anxiety disorders. It is speculated that a bi-directional relationship exists, developed by a series of genetic, environmental, clinical and neurobiological factors. Treatment of mood disorders can be more complicated in the presence of overweight and obese individuals. However, obesity alone increases the risk of depressive symptoms and manic attacks.

Additionally, depressive symptoms are observed in individuals regardless of age, sex and race who aim in obesity treatment or developed medical conditions associated with obesity like T2DM, coronary artery disease, cerebrovascular disease, musculoskeletal disorder and several forms of cancer. Drugs used in the therapy of other medical conditions that co-exist with obesity may influence and induce mood depressive behaviors. Referring to the high impact of psychiatric diseases and obesity in morbidity and disability, the concomitance of these conditions indicates the arousal of accumulative effect in the burden of illness (Mansur, Brietzke & McIntyre, 2015)

Several mechanisms are involved in the explanation of the relationship between obesity and psychiatric disorders and have been investigated for a long period of time, in order to find a way to render them more understandable. The most common dysregulated biological pathways include disturbances in HPA axis, an increase in oxidative and nitrosative stress, reduced antioxidant defenses and dysregulation of inflammatory pathways leading to apoptosis, mitochondrial abnormalities, neurodegeneration and reduced neuronal plasticity and neurogenesis (Lopresti & Drummond, 2013a).

All the above-mentioned abnormalities are influenced by environmental, genetic, psychological factors, as well as social and lifestyle parameters.

The present review is focused on the relationship between metabolic abnormalities and psychiatric disorders analyzing the similarities in their biological pathways.

2. Epidemiology

Obesity, which causes a series of physical problems in patients, shows a dramatic increase over the past three decades. The disease of obesity is one of the most important disorders of the human body that affects the modern developed societies and represents the large increase in the atomic weight and a particularly excessive increase in body fat; approximately 15 to 20 pounds above the normal weight (Oken & Gillman, 2003). Obesity is a modern scourge that tends to get the global epidemic. The incidence of obesity is increasing rapidly and more than 30% of adults in Western society are obese while equally worrying is the increase of obesity in childhood and adolescence.

Research studies have focused either on the examination of obesity prevalence in people with mental disorders or on the examination of mental disorders in obese people (Taylor et al., 2008; Scott et al., 2008).

Epidemiologic data suggest an association between obesity and mood disorders while few of them have investigated the relationship between BMI and psychopathology. Simon et al (2006) and Onyike et al (2003) found that BMI increases the risk of major depression even when controlling for demographic characteristics and that obesity is linked to increased odds of anxiety disorders. There are gender differences in obesity among men and women. Men are more likely to be overweight (Hedley et al., 2004), while on the other hand women tend to be obese (Poulose et al., 2005).

Barry, Pietrzak & Petry (2008) have found that BMI>30 is associated with increased odds of developing any mood disorder (including major depressive disorder and dysthymic disorder and specific phobia) both in women and men. They also found that obese women were at risk of developing bipolar I and II disorders and social phobia unlikely men. Desai et al (2009) study aimed to investigate the gender differences and the association between BMI and psychopathology based on data from the National Epidemiologic Study of Alcohol and Related Conditions. They found that both obese men and women were more likely to develop anxiety disorders, but the association was more statistically significant for women.

Carpenter et al (2000) investigated the gender impact on the association of obesity and depression on data over 40.000 American adults and concluded that a significant positive association between BMI and depression in women exists and a significant negative association in men. Simon et al (2006) epidemiological study concluded that obesity (BMI ≥ 30) elevates the odds of developing anxiety and mood disorders both in men and women in contrast to non-obese (BMI < 30) men and women.

Simultaneously, women with a lifetime history of the disorder or major depression had been associated with greater likelihood of developing obesity (McIntyre et al., 2006). Also, obese adolescent and young female are of greater likelihood of experience anxiety disorders (Anderson et al., 2007; Lamertz et al., 2002). According to Weissman et al (1993) women are more likely to experience mood disorders. Chen, Jiang & Mao (2009) study have identified that obesity is associated with 30-40% increase in depression, mainly in women of age 18-39 years.

Based on this evidence it could be mentioned that BMI and psychopathology seem to be more strongly associated in women than in men (McIntyre et al., 2006; Carpenter et al., 2000). Also, Atlantis & Baker (2008) systematic review have argued that longitudinal studies show that obesity increases the risk of developing depression. The review results regarding the association between obesity and depression for U.S. population were referred to women and not men.

Several studies have mentioned the existence of obesity in adults with mental disorders (Zhao et al., 2009; Onyike et al., 2003), stating the use of some antidepressants is positively related to obesity (Aronne & Segal, 2003). CDC statistical data shows that adults with depression were more likely to be obese than adults without depression. Furthermore, women with depression have higher odds to be obese than women without depression. For men with depression those who are aged over 60, there are higher odds to develop obesity while for both genders the younger adults aged 20–39 are less likely to be obese in contrast to people over 40 (Pratt & Brody, 2014).
Few studies have reported the association between age and increased odds of developing obesity and mental health disorders (Ma & Xiao, 2009; van der Merwe, 2007). The age group, which is at greater risk, is young women while older people could be also at greater risk given the health problems arising from age (Kivimaki et al., 2009).
Regarding ethnic groups, it has been suggested that the association of obesity and mood disorders, especially depression, varies across ethnic groups. Women citizens of U.S. non-Hispanic white and black women are at greater risk of developing obesity-related to depression (Gavin, Rue & Takeuchi, 2010). Simon et al (2006) did not note gender differences between obesity and mood disorders association. However, their study identified differences across racial groups and education levels.

Table : Percentage of adults aged 20 and over who were obese, by age, sex, and depression status in the US for the period 2005-2010 in accordance to Pratt & Brody (2014).

The association between depression and obesity has been studied among Western countries population and the meta-analysis of de Wit et al (2010) have shown the positive association in general adult population which has been more markedly pronounced among women than men. Another two meta-analyses of longitudinal studies found that depression is positively associated with abdominal obesity (Xu, Anderson & Lurie-Beck, 2011; Luppino et al., 2010).

Abou Abbas et al (2014) meta-analysis was based on the synthesis of data from observational studies and aimed to evaluate the association between depression and obesity in Middle Eastern countries. The meta-analysis of 8 observational studies suggests the positive association between depression and obesity among adults in Middle Eastern countries while it has been found that the association is statistically more significant among women.

Pratt & Brody (2014) study for U.S. adults have shown that 45% of non-Hispanic white women with depression were obese and among Mexican-American and non-Hispanic black men and women obesity rated did not differ by depression status.

Regarding the association between antidepressant medication and obesity, 50% of U.S women with severe depressive symptoms were obese while more than 50% of both gender adults with moderate to severe depressive symptoms who were also treated with antidepressant medication were obese (Pratt & Brody, 2014).

Finally, the association between obesity and socioeconomic status seems to be still unclear while Minet Kinge & Morris (2010) study reported the association of lower socioeconomic status with a greater risk of obesity and depression (Chen, Jiang & Mao, 2009). On the other hand, Simon et al (2006) and Moore, Stunkard A, Srole (1962) have found that high socioeconomic status is related to obesity and depression.

3. Metabolic abnormalities involved in mental disorders

Metabolic syndrome is involved to risk factors for development obesity, insulin resistance, glucose intolerance, and dyslipidemias. Recent evidence shows that patients with mood disorders, such as schizophrenia, have higher odds to develop metabolic syndrome (Stubbs et al., 2015; Zhang et al., 2015; Harris et al., 2013).

Figure 2, represents the pathways through which obesity and psychiatric disorders are associated



Figure : Οbesity and its influence on pathways associated with psychiatric disorders.





Dyslipidemia

The metabolic syndrome is the result of the complex of metabolic abnormalities and is correlated with obesity while evidence shows that psychosocial environment conduces to obesity development (Iwasaki et al., 2008).

Table 1: The definitions of metabolic syndrome (Saravane, 2012).

*or treated with antihypertensive medication

**or treated with insulin or hypoglycemic medication

While the prevalence of metabolic syndrome in the general population is estimated 2-6% (is more frequent in men) (Maumus et al., 2005), in patients with schizophrenia and mood disorders estimates up to 36%. More specifically, the recent meta-analysis of Mitchell et al (2013) on 25.692 total patients showed that the overall rate of metabolic syndrome in mood disorders and schizophrenia is 32.5%. De Hert et al (2006) reported an estimated range of 36% in schizophrenics taking antipsychotics and Yumru et al (2012) reported 32% bipolar patients with metabolic syndrome.

The main feature of metabolic syndrome is obesity which leads to dyslipidemia and insulin resistance. Wysokinski, Kowman & Kłoszewska (2012) have mentioned that dyslipidemia and raised fasting plasma glucose is common in schizophrenics and individuals with mood disorders. It should be highlighted that many patients with mood disorders and schizophrenia do not receive the appropriate treatment for metabolic abnormalities.

Nasrallah (2008) reports that the 88% of patients with dyslipidemia were not receiving treatment of metabolic syndrome as 38% of that had diabetes and 62% hypertension.

This evidence is leading to the suggestion that lipids and blood levels of mood disorders and schizophrenia patients should be frequently monitored (Wysokiński, Strzelecki & Kłoszewska, 2015).

Bipolar disorder and schizophrenia are linked to metabolic abnormalities, which include obesity, increased glucose blood levels and raised lipids. Metabolic syndrome seems to be more frequent on patient with mood disorders taking psychotropic agents including antidepressants, mood stabilizers and antipsychotics (McIntyre et al., 2010; Teixeira & Rocha, 2007; De Hert et al., 2006).

Wysokiński, Strzelecki & Kłoszewska (2015) research study aimed to examine the differences in HDL, LDL, glucose, cholesterol and triglycerides levels in patients with schizophrenia and bipolar disorder. The research study involved 2305 Caucasian patients with schizophrenia, bipolar depression, bipolar disorder and bipolar mania and found that there is a high prevalence of lipid and glucose abnormalities in schizophrenics and mood disorder patients.

Also, it has been shown that patients with schizophrenia and bipolar depression presented the higher level of TGA while schizophrenia and bipolar disorder are linked to increased risk of TGA level exceeding the upper normal limit (150 mg/dL). De Leon et al (2007) had found higher TGA level in schizophrenics than Wysokiński, Strzelecki & Kłoszewska (2015) (139.8 mg/ dL).

The main feature of the metabolic syndrome is the resistance to insulin action or insulin resistance, which is frequent in obese people. Insulin resistance is defined as the situation in which the tissues of the body do not react to insulin secretion from pancreas as it is expected in normal conditions. Insulin resistance results from the reduced clearance of free fatty acids in plasma. Overall the lipid profile of an obese individual, because of the insulin resistance, is likely to have higher levels of VLDL and LDL cholesterol, triglycerides and decreased levels of HDL cholesterol (Wilson et al., 2002; Ferrannini et al., 1991).

The metabolic syndrome causes the abdominal fat distribution (mainly visceral adiposity), which is a risk factor for glucose intolerance, insulin resistance, and dyslipidemia. Additionally, adipose, muscle, nervous, adrenal and hepatic tissues could be affected and vasculature could be significantly affected. Lipoprotein abnormalities and insulin resistance are a major problem caused by metabolic syndrome and the insulin resistance contributes to glucose intolerance.

The unchecked lipolysis could lead to raised delivery of free fatty acids to the liver for triglyceride synthesis and packaging into very low-density of VLDL particles. Lower HDL levels are associated to higher VLDL as the reciprocal exchanges between these lipoproteins mediated by cholesterol ester transfer protein.

Also, visceral obesity is an initial marker of metabolic syndrome while insulin resistance is linked to increasing plasma triglycerides, increased blood pressure, impaired glucose control, reduced high-density of HDL cholesterol, increased markers of inflammation and increased risk of blood clotting. Thus, elevated fasting plasma triglycerides as an indicator of insulin resistance could be used as a key point for monitoring patient's risk (Nasrallah, 2008).

As LDL is formed small and thick because of increased neutral transfer between different classes of lipids and consequent increased activity of CETP enzyme (protein transfer of cholesterol esters), the risk of atherogenesis is increased. Insulin stimulates the formation of various growth factors such as Insulin-Like Growth-factor I, which contributes to atherosclerosis (Wilson et al., 2002; Ferrannini et al., 1991).
Glucose disturbances
There is a debate between scientists for whether metabolic syndrome is a result of antipsychotic medication or schizophrenia per se (Britvicet al., 2013). There is a suggestion of the existence of glucose and lipid metabolism abnormalities at the onset of psychosis.
More specifically, Wu et al (2013) have found that in first-episode schizophrenia patients there was higher insulin, insulin resistance and C-peptide levels and lower total cholesterol, high-density lipoprotein cholesterol and apolipoprotein A1 levels.
The insulin resistance is characterized by the impaired response to insulin action in relation to the metabolism of carbohydrates and is regarded as a key atherosclerotic risk factor. Several studies indicate the relationship between major depression disorder and insulin resistance. One of the pathophysiological mechanisms correlates insulin resistance with depression caused by the overactivity of HPA axis (Ramasubbu, 2002).
There is a recent suggestion that schizophrenics have impaired fasting glucose tolerance and were more insulin resistant and had higher fasting 2-h plasma glucose levels (Fernandez-Egea et al., 2009; Spelman et al., 2007; Ryan et al., 2003). Guest et al (2010) have found that first onset schizophrenia patients had increased circulating levels of insulin-related peptides and the secretory granule protein chromogranin A. Their later study showed that schizophrenics (both first and recent onset schizophrenia patients) had increased serum concentrations of insulin and chromogranin A.

The role of kynurenine pathway

Obesity is associated with upregulation of the kynurenine pathway, evidenced by decreased concentrations of plasma tryptophan and an increased kynurenine/tryptophan ratio (Brandacher et al., 2007). Upregulation in the kynurenine pathway affects neurotransmitter production, especially serotonin. Moreover, it is associated with increased oxidative stress and neurodegeneration. The dysregulation of this pathway is suggested to be important in depression, schizophrenia and bipolar disorder (Myint et al., 2012; Lopresti et al., 2013b).

The tryptophan catabolite pathways (TRYCAT) are an important mediator of the association of oxidative and nitrosative stress and immuno-inflammatory activation with alterations in glia-neuronal interactions and neuronal activity. An emerging concurrence proposes that oxidative and nitrosative stress is interacting with changes in immuno-inflammatory activity, increasing levels of proinflammatory cytokines, in turn activating indoleamine 2,3-dioxygenase (IDO). This forces tryptophan down the tryptophan catabolite pathways, decreasing serotonin and melatonin production, in sequence increasing depression and metabolic dysregulation . Here again alterations on leptin is proposed to be the mediator that driving changes in the tryptophan catabolite pathway, both centrally and peripherally and in the fragile balance between TRYCAT products and induction of metabolic regulators. This is a mechanism underestimating the metabolic syndrome and psychiatric disorders (Anderson and Maes ,2013).

Finkelstein et al., observed a decrease free tryptophan in the plasma of obese rats. Plasma tryptophan concentrations were decreased in obese patients regardless of dietary intake or weight reduction. (Brandacher et al.,2007). Preoperative kynurenine/tryptophan ratio in morbidly obese patients was significantly increased compared to the healthy individuals, and postoperative weight reduction did not normalize kynurenine/tryptophan ratio. In addition, these tryptophan metabolic changes may subsequently reduce serotonin production and cause mood complications, depressive symptoms, and impaired satiety ultimately leading to obesity (Brandacher et al.,2006; Oxenkrug,2010).