Immune changes and neurotransmitters: Possible interactions in depression?

https://doi.org/10.1016/j.pnpbp.2012.10.006Get rights and content

Abstract

A disturbed metabolism of catecholamines and other neurotransmitters appears to play a major role in the pathogenesis of neurospychiatric symptoms, such as changes in mood and depression. This symptomatology is common in patients with chronic inflammatory disorders such as infections, autoimmune diseases, or cancer. The pathogenesis of these symptoms is still unclear. Pro-inflammatory stimuli interfere not only with the neural circuits and neurotransmitters of the serotonergic system but also with those of the adrenergic system. The pro-inflammatory cytokine interferon-γ stimulates the biosynthesis of 5,6,7,8-tetrahydrobiopterin (BH4), which is a co-factor for several aromatic amino acid mono-oxygenases and is rate-limiting for the biosynthesis of the neurotransmitter serotonin and the catecholamines dopamine, epinephrine (adrenaline) and norepinephrine (noradrenaline). Interferon-γ triggers the high output of reactive oxygen species in macrophages, which can destroy the oxidation-labile BH4. Recent data suggests that oxidative loss of BH4 in chronic inflammatory conditions can reduce the biosynthesis of catecholamines, which may relate to disturbed adrenergic neurotransmitter pathways in patients.

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

References (115)

  • M. Kamata et al.

    Genetic polymorphisms in the serotonergic system and symptom slusters of major depressive disorder

    J Affect Disord

    (2011)
  • S. Kapur et al.

    Role of the dopaminergic system in depression

    Biol Psychiatry

    (1992)
  • J.C. Kaski et al.

    Elevated serum neopterin levels and adverse cardiac events at 6 months follow-up in Mediterranean patients with non-ST-segment elevation acute coronary syndrome

    Atherosclerosis

    (2008)
  • Y.K. Kim et al.

    Cytokine imbalance in the pathophysiology of major depressive disorder

    Prog Neuropsychopharmacol Biol Psychiatry

    (2007)
  • F.E. Lotrich et al.

    Risk for depression during interferon-alpha treatment is affected by the serotonin transporter polymorphism

    Biol Psychiatry

    (2009)
  • C. Murr et al.

    Inverse association between serum concentrations of neopterin and antioxidants in patients with and without angiographic coronary artery disease

    Atherosclerosis

    (2009)
  • G. Neurauter et al.

    Serum phenylalanine concentrations in patients with ovarian carcinoma correlate with concentrations of immune activation markers and of isoprostane-8

    Cancer Lett

    (2008)
  • F. Nourhashemi et al.

    Alzheimer disease: protective factors

    Am J Clin Nutr

    (2000)
  • R.W. Powers et al.

    Plasma homocysteine concentration is increased in preeclampsia and is associated with evidence of endothelial activation

    Am J Obstet Gynecol

    (1998)
  • C.L. Raison et al.

    Cytokines sing the blues: inflammation and the pathogenesis of depression

    Trends Immunol

    (2006)
  • J.J. Strik et al.

    One year cumulative incidence of depression following myocardial infarction and impact on cardiac outcome

    J Psychosom Res

    (2004)
  • P.G. Surtees et al.

    Social adversity, the serotonin transporter (5-HTTLPR) polymorphism and major depressive disorder

    Biol Psychiatry

    (2006)
  • F. Tatzber et al.

    Elevated serum neopterin levels in atherosclerosis

    Atherosclerosis

    (1991)
  • A.R. Van Gool et al.

    Serum amino acids, biopterin and neopterin during long-term immunotherapy with interferon-alpha in high-risk melanoma patients

    Psychiatry Res

    (2003)
  • D.N. Anderson et al.

    Recovery from depression after electroconvulsive therapy is accompanied by evidence of increased tetrahydrobiopterin-dependent hydroxylation

    Acta Psychiatr Scand

    (1994)
  • P. Avanzas et al.

    Elevated serum neopterin predicts future adverse cardiac events in patients with chronic stable angina pectoris

    Eur Heart J

    (2005)
  • M.I. Botez et al.

    Folate deficiency and decreased brain 5-hydroxytryptamine synthesis in man and rat

    Nature

    (1979)
  • T. Bottiglieri et al.

    Homocysteine, folate, methylation, and monoamine metabolism in depression

    J Neurol Neurosurg Psychiatry

    (2000)
  • C.J. Boushey et al.

    A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes

    J Am Med Assoc

    (1995)
  • E. Bromet et al.

    Cross-national epidemiology of DSM-IV major depressive episode

    BMC Med

    (2011)
  • M.L. Bruce et al.

    The impact of depressive symptomatology on physical disability: MacArthur studies of successful aging

    Am J Public Health

    (1994)
  • S.J. Bull et al.

    Functional polymorphisms in the interleukin-6 and serotonin transporter genes, and depression and fatigue induced by interferon-alpha and ribavirin treatment

    Mol Psychiatry

    (2008)
  • A. Caspi et al.

    Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene

    Science

    (2003)
  • A. Cervilla et al.

    The risk for depression conferred by stressful life events is modified by variation at the serotonin transporter 5HTTLPR genotype: evidence from the Spanish PREDICT-Gene cohort

    Mol Psychiatry

    (2007)
  • X.J. Chang et al.

    Serum and erythrocyte amino acid pattern: studies on major burn cases

    Burns Incl Therm Inj

    (1983)
  • D.S. Charney et al.

    Life stress, genes, and depression: multiple pathways lead to increased risk and new opportunities for intervention

    Sci STKE

    (2004)
  • M.J. Connor et al.

    The identification of p-acetamiobenzoate as a folate degradation product in rat urine

    Biochem J

    (1979)
  • R. Dantzer et al.

    From inflammation to sickness and depression: when the immune system subjugates the brain

    Nat Rev Neurosci

    (2008)
  • H. Denz et al.

    Correlation between neopterin, interferon-gamma and haemoglobin in patients with haematological disorders

    Eur J Haematol

    (1990)
  • L. Devoino et al.

    Participation of serotoninergic system in neuroimmunomodulation: intraimmune mechanisms and the pathways providing an inhibitory effect

    Int J Neurosci

    (1988)
  • L. Devoino et al.

    Dopaminergic stimulation of the immune reaction: interaction of serotoninergic and dopaminergic systems in neuroimmunomodulation

    Int J Neurosci

    (1988)
  • J. Du et al.

    The protein partners of GTP cyclohydrolase I in rat organs

    PLoS One

    (2012)
  • J.W. Eikelboom et al.

    Homocyst(e)ine and cardiovascular disease: a critical review of the epidemiologic evidence

    Ann Intern Med

    (1999)
  • T.C. Eley et al.

    Gene–environment interaction analysis of serotonin system markers with adolescent depression

    Mol Psychiatry

    (2004)
  • D. Fuchs et al.

    Decreased serum tryptophan in patients with HIV-1 infection correlates with increased serum neopterin and with neurologic/psychiatric symptoms

    J Acquir Immune Defic Syndr

    (1990)
  • D. Fuchs et al.

    Is hyperhomocysteinemia due to the oxidative depletion of folate rather than to insufficient dietary intake?

    Clin Chem Lab Med

    (2001)
  • I.H. Gotlib et al.

    HPA axis reactivity: a mechanism underlying the associations among 5-HTTLPR, stress, and depression

    Biol Psychiatry

    (2008)
  • T.B. Grammer et al.

    Neopterin as a predictor of total and cardiovascular mortality in individuals undergoing angiography in the Ludwigshafen Risk and Cardiovascular Health study

    Clin Chem

    (2009)
  • B. Halliwell

    Reactive oxygen species in living systems: source, biochemistry, and role in human disease

    Am J Med

    (1991)
  • T. Harada et al.

    Feedback regulation mechanisms for the control of GTP cyclohydrolase I activity

    Science

    (1993)
  • Cited by (106)

    • Psychoneuroimmunology

      2023, Stress: Immunology and Inflammation: Handbook of Stress Series Volume 5
    View all citing articles on Scopus
    View full text