Progress in Neuro-Psychopharmacology and Biological Psychiatry
Immune changes and neurotransmitters: Possible interactions in depression?
Highlights
► Immune activation, the serotonin and the kynurenic acid pathway are linked via IDO. ► Breakdown of tryptophan by IDO seems insufficient to explain types of depression. ► Chronic immune activation correlates with moderately increased serum phenylalanine. ► Increased Phe/Tyr implies a reduced activity of phenylalanine hydroxylase (PAH). ► Immune biomarkers plus Phe/Tyr and Kyn/Trp as tools for personalized medicine.
Introduction
Major depressive disorder (MDD) is a heterogeneous disease characterized by low mood and anxiety, loss of interest and pleasure in normally enjoyable activities, as well as loss of energy. Neurocognitive impairment, neurovegetative and somatic symptoms are also common clinical symptoms of MDD.
In high income countries, the average lifetime prevalence of MDD is approximately 15% countries. Approximately 5.5% of the general population has been diagnosed within the past 12 months (Bromet et al., 2011). The World Health Organization (WHO) ranks MDD as the fourth leading cause of disability worldwide and projects that by 2030, it will be the second leading cause (Mathers and Loncar, 2005). MDD represents a serious and often recurrent disorder. Depressed patients experience reduced general functioning and quality of life, as well as increased physical morbidity and mortality (Spijker et al., 2004, Üstün et al., 2004). Several studies have shown that MDD predicts the onset and the progression of both physical and social disability (Bruce et al., 1994, Penninx et al., 1998). The 12-month prevalence rates of mental disorders, especially MDD, are 1.5 to 2 times higher in patients with chronic somatic diseases compared to the general population (Harter et al., 2007). In general hospitals, depressive disorders are present in 10 to 60% of somatically ill patients, depending on the somatic diagnosis. In the first month after myocardial infarction, the incidence for MDD increases between 15% and 30% (Strik et al., 2004) and systematic reviews of prognostic studies have identified co-morbid depression as a consistent predictor of adverse outcome, including mortality (Kuper et al., 2002, Strik et al., 2004).
In contrast to this significant burden of disease, rates of diagnostic recognition of MDD are poor (35%–45%) (Hansen et al., 2001, Hardman et al., 1989, Harter et al., 2004, Ormel et al., 2008, Wancata et al., 2000). Furthermore, only a part of diagnosed patients are provided with adequate treatment. Ormel et al. (2008) found that in high-income countries severely disabling mental disorders are only half as likely to be treated, compared to serious disabling physical disorders (35.3% vs. 77.6%).
Although the exact pathophysiological mechanism of MDD is still not known, dysfunction in the monoamine systems of neurotransmitters 5-HT, NE and DA appears to be involved in the pathogenesis when monoamine depletion was found to influence mood. Evidence for this hypothesis came from clinical observations and animal experiments, which showed that the antihypertensive drug reserpine, which causes a depletion of presynaptic stores of NE, 5-HT, and DA, induced a syndrome resembling depression. In contrast to the effects obtained with reserpine, euphoria and hyperactive behavior were observed in some patients being treated with iproniazid, a compound synthesized for the treatment of tuberculosis, which increased brain concentrations of NE and 5-HT by inhibiting the metabolic enzyme MAO. These findings were the basis for the development of tricyclic antidepressant agents to influence the monoaminergic neurotransmission in the 50s, followed by the design of serotonergic reuptake inhibitors in the 80s; more recently substances inhibiting the noradrenergic reuptake have become available.
Research on the pathophysiology of MDD revealed that acute monoamine depletion did not decrease mood in healthy controls but only in individuals with a family history of major depressive disorder (Ruhé et al., 2007). This indicates that a monoamine deficiency itself is not sufficient for the development of the clinical syndrome of depression.
MDD represents a complex psychiatric disorder, which is also influenced by psychosocial, environmental, and genetic conditions (Fig. 1). Although it has been difficult to identify single candidate genes, the influence of genetic factors on the development of MDD has been proven in numerous studies, e.g. the promoter region of the 5-HT transporter gene (5-HTTLPR) (Caspi et al., 2003, Cervilla et al., 2007, Eley et al., 2004, Kaufmann et al., 2004, Wilhelm et al., 2006) and 5-HT receptor polymorphisms (Kamata et al., 2011). Furthermore, gene–environment interactions showing a relationship between stressful life events and serotonergic genotypes have been reported (Surtees et al., 2006, Uher and McGuffin, 2008). In this context, it has been found that individuals who are homozygous for the short allele of the 5-HTTLPR polymorphisms have an increased activity of the hypothalamic–pituitary–adrenal axis due to psychosocial stress (Gotlib et al., 2008, Jabbi et al., 2007). Present research also focuses on genetic polymorphisms of different enzymes catalyzing the catecholaminergic pathways. Kim et al., 2006 showed that the monoamine transporter gene polymorphisms, 5-HT transporter, and NET are associated with a response to antidepressants with homologous monoamine transporter targets. Combinations of polymorphisms were informative for response and non-response.
Until recently, the role of DA in the etiopathology and treatment of depression (Bottiglieri et al., 2000, Kapur and Mann, 1992, Stein, 2008) was largely ignored. This occurred despite a dopaminergic theory of depression which was proposed more than 35 years ago (Braestrup et al., 1975).
Aside from the dysfunction in the neurotransmitter systems of 5-HT, NE and DA, MDD is associated with a hypothalamic–pituitary–adrenal (HPA) “hyperdrive”. Signs and symptoms characteristic for depression include changes in the setpoint of the HPA-system, which in the majority of patients result in an altered regulation of corticotropin (ACTH) and cortisol secretory activity. Knowledge on the functioning of the HPA axis under acute or chronic challenge is also a key to understand the intimate link between stress response and the pathogenesis of depression (Charney and Manji, 2004). Despite the fact that observed changes of HPA regulation are so far not specific for the diagnosis of depression or for any of its clinical syndromes (Holsboer, 2008), altered HPA-axis parameters are considered important biomarkers, particularly in preclinical studies (Fig. 1).
Section snippets
Depression and inflammation
During the past 20 years the relationship between depressive symptoms and somatic conditions such as cardiovascular disease, diabetes, cancer, and neurodegenerative disorders has received increasing attention in research. Depressive symptoms may be a secondary reaction to the development of the disease, the disease itself, or to complications and aversive symptoms of the disease; in addition, they may also be related to side effects of medications administered to treat the illness. Aside from
5,6,7,8-Tetrahydrobiopterin (BH4) and the link between immune activation and neurotransmitter biosynthesis
The pteridine derivative 5,6,7,8-tetrahydrobiopterin (BH4) may represent a key compound which is deeply involved in the biochemistry of neurotransmitter synthesis, including nitric oxide, and it is also affected by oxidative stress (Fig. 3). BH4 is the co-factor of the aromatic amino acid mono-oxygenases phenylalanine 4-hydroxylase (EC 1.14.13.39; PAH), tyrosine 5-hydroxylase (EC 1.14.16.2), tryptophan 5-hydroxylase (EC 1.14.16.4), of nitric oxide (NO) synthases (EC 1.14.13.39) (Werner-Felmayer
Phenylalanine 4-hydroxylase
The essential aromatic amino acid phenylalanine is substrate for PAH, which forms another important amino acid namely tyrosine (Fig. 4). Tyrosine is the precursor for the biosynthesis of DOPA and the catecholamines DA, epinephrine and norepinephrine. For the enzymatic hydroxylation of phenylalanine into tyrosine by PAH, the non-protein cofactor BH4 is required as a hydrogen donor. During the hydroxylation reaction, hydrogen atoms of BH4 are used to reduce the molecular oxygen for hydroxylation
Monitoring of immune system activation
During the pro-inflammatory immune responses, various mediators, the so-called cytokines, are released by cells upon activation. Among them, interleukin-2 and IFN-γ are characteristic for Th1-type immunity (Romagnani, 2001). IFN-γ is essential for antimicrobial and tumoricidal mechanisms in target cells such as macrophages and as a consequence, several enzyme pathways are activated including NO synthase, GCH and IDO. IFN-γ is also the most important trigger for the formation and release of
Immune system activation, oxidative stress and moderate hyperphenylalaninemia
In monocyte-derived macrophages, Th1-type cytokine IFN-γ strongly induces the release of ROS within the so-called oxidative burst reaction (Nathan et al., 1983) as it stimulates neopterin formation in parallel. Thus, one can expect that, in clinical conditions which are linked to high neopterin production, the concomitant production of ROS will place an additional burden on antioxidant defense systems. Moreover, neopterin itself enhances the oxidizing capacity of antimicrobial molecules and
Clinical implications
Conditions of chronic non-resolving inflammation represent the underlying causes for chronic somatic diseases, such as cardiovascular disease, diabetes, cancer, as well as depression and might be due to factors like early-life-stress, other psychosocial stressors, adiposity, diet, and gut microbiota (Haroon et al., 2012). The immune mechanisms involved in the pathophysiological processes include networks between endocrine, autonomic and neurotransmitter systems (Fig. 2). Inflammatory processes
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