Depression and the role of genes involved in dopamine metabolism and signalling

Abstract

Major depressive disorder (MDD) is a common psychiatric disorder and leading cause of disability worldwide. It is associated with increased mortality, especially from suicide. Heritability of MDD is estimated around 40%, suggesting that genotyping is a promising field for research into the development of MDD. According to the dopamine theory of affective disorders, a deficiency in dopaminergic neurotransmission may play a role in the major symptoms of MDD. Specific polymorphisms in genes that affect dopamine transmission could increase susceptibility to MDD. To determine the extent to which these genes influence vulnerability to MDD, we discuss genes for crucial steps in dopamine neurotransmission: synthesis, signalling and inactivation. The val158met polymorphism of the COMT gene exemplifies the lack of consensus in the literature: although it is one of the most reported polymorphisms that relates to MDD vulnerability, its role is not corroborated by meta-analysis. Gene–gene interactions and gene–environment interactions provide more explanatory potential than single gene associations. Two notable exceptions are the DRD4 and DAT gene: both have variable tandem repeat polymorphisms which may have a “single gene” influence on susceptibility to MDD.

Introduction

Major depressive disorder (MDD) is a common psychiatric disorder that has been predicted to become the second leading cause of disability worldwide by 2020 (Murray and Lopez, 1996). It is associated with increased mortality, especially from suicide (Harris and Barraclough, 1998, Schneider et al., 2001). In order to develop new pharmacotherapeutic strategies it is crucial to comprehensively understand the aetiology of MDD. Part of the phenotypic variation of MDD is genetic: twin studies estimate the heritability of MDD around 40% (Sullivan et al., 2000) or even higher (Kendler et al., 2001). Therefore, genetics are a promising field for research into aetiology of MDD.

On the longer term, knowledge of genetic variance associated with MDD might aid treatment strategies. The concept of personalised medicine (Langreth and Waldholz, 1999), originally formulated for oncological drugs, recommends that people be treated with drugs that suit their personal genotype. This might also be of relevance in psychiatry as a poor treatment response often results from giving every patient the same treatment (Lin et al., 2008). It has even been shown that patient stratification based on genetically determined aspects of personality could be employed to maximize the response to antidepressant treatment (Joyce et al., 1994). In sum, specific genotyping is important in the battle against MDD for two main reasons: (i) generation of a good model of MDD aetiology and (ii) patient stratification in the framework of personalised medicine.

Most genetic studies in MDD have until now focused on genes regulating the serotonergic neuromodulatory system. A meta-analysis on genetic association studies in MDD (Lopez-Leon et al., 2008) showed however that of the genes involved in serotonergic neurotransmission only one (the serotonin transporter gene, SLC6A4) showed a significant association. However, this area continues to be contentious (Risch et al., 2009).

Despite the large focus on the serotonin system, already in 1965 it was postulated that dopamine is involved in MDD (Schildkraut, 1965) and since then the idea that prominent symptoms of MDD arise at least in part from disturbances in dopamine neurotransmission has been reiterated in the literature many times (Brown and Gershon, 1993, Diehl and Gershon, 1992, Dunlop and Nemeroff, 2007, Schildkraut, 1974, Schildkraut and Kety, 1967). Indeed, a considerable body of historical and recent evidence is consistent with this idea. First, to meet the criteria of a major depressive episode (MDE), at least five symptoms need to be present during the same 2-week period. These symptoms are listed in Table 1 (American Psychiatric Association, 2007).

Strikingly, disturbances in processes regulated by dopamine are known to lead to similar symptoms. Dopamine regulates the reward system (Lippa et al., 1973, Wise, 1978), specifically mood (Ashby et al., 1999), motivation (Blackburn et al., 1992, Wise and Bozarth, 1984), attention (Nieoullon, 2002), decision making (Assadi et al., 2009), and psychomotor speed (Poirier et al., 1975). Dopamine release in the ventral striatum is also correlated with the euphoric response to amphetamines (Drevets et al., 2001). Euphoria is the opposite feeling of dysphoria and dysphoria is an important symptom of a MDE. Therefore, dysphoria may be linked to dopamine neurotransmission. Amphetamines are used as pharmacological drug in the treatment of narcolepsy and obesity (Berman et al., 2009), which underscores the role of dopamine in weight control and sleep regulation. Second, antidepressants that are precursors in the biosynthesis of dopamine, dopamine agonists and dopamine re-uptake inhibitors all improve depressive symptoms (Kapur and Mann, 1992). For example, the dopamine agonist pramipexole was found to have antidepressant effects in MDD and bipolar disorder (Corrigan et al., 2000, Goldberg et al., 2004, Zarate et al., 2004). Conversely, dopamine depletors and antagonists reduce motivation and mood and induce a depressed state (Bressan et al., 2002, Verhoeff et al., 2003). Third, dopamine levels are influenced by stress (Corrodi et al., 1971, Pani et al., 2000) and stress is a well-known factor in the aetiology of MDD. Indeed, stress-induced dopamine release has been shown to be tightly coupled to neuroendocrine stress responses (e.g. elevated plasma corticosterone levels, Sullivan and Gratton, 1998). Finally, depression also arises as secondary symptom of diseases which are strongly associated with dopamine depletion such as Parkinson's disease (Cummings, 1992) and drug addiction (Volkow, 2004).

Disturbances in dopamine transmission could result from either disturbed dopamine release from presynaptic neurons, impaired signalling, or disturbed catabolism. Therefore, in order to shed light on the role of dopamine in MDD, we focus on proteins involved in dopamine metabolism and the main signalling steps; these include the dopamine receptors and transporters. In principle, any gene variant for a protein involved in dopamine neurotransmission provides a potential cause of a congenital proneness to MDD. In addition any one of these genes is a potential therapeutic target.

Neurotransmission is a complex phenomenon involving the interplay of several processes. There are many other genes influencing dopamine neurotransmission like vesicular monoamine transporter (VMAT, Erickson et al., 1992), organic cation transporters (OCT, Ciarimboli, 2008), but for this review we will focus on the following processes: (1) biosynthesis of the neurotransmitter, (2) interaction of the neurotransmitter with specific receptors located on postsynaptic membranes, and (3) removal of the transmitter via enzymatic degradation or via specialized transporter proteins on presynaptic terminal.

The biosynthesis of dopamine (Fig. 1) depends on availability of the amino acid tyrosine, which is converted to dihydroxyphenylalanine (dopa) by the enzyme tyrosine hydroxylase (TH, Nagatsu et al., 1964). Subsequently, the enzyme dopa decarboxylase (DDC) rapidly catalyzes formation of dopamine from dopa. DDC is also called aromatic l-amino acid decarboxylase (Lovenberg et al., 1962), because it also acts on other aromatic amino acids, such as tryptophan. In neurons that use dopamine as a neurotransmitter, no further enzymatic modification occurs. In some neurons, dopamine is substrate for dopamine-β-hydroxylase (DBH). DBH converts dopamine to norepinephrine, which in turn can be transformed into epinephrine by phenylethanolamine-N-methyltransferase (PNMT, Kopin, 1968).

After release from the terminal, dopamine binds to and activates G-protein-coupled receptors on synaptic and extrasynaptic membranes and thereby exerts its effects. There are five subtypes of dopamine receptors which can be divided into two groups, the dopamine D1-like receptors (receptors D1 and D5) and the dopamine D2-like receptors (receptors D2, D3 and D4). The D1 and D2 receptors were the first receptors that have been discovered and the later discovered dopamine receptors show high homology with D1 and D2 (Jackson and Westlind-Danielsson, 1994). D1-like receptors activate the adenylate cyclase second messenger system, leading to an increase in intracellular cyclic adenosine monophosphate (cAMP) concentrations. cAMP increases protein kinase A activity with resulting functional changes of enzymes and other proteins within the cell. The D2-like receptors, when stimulated, all inhibit adenylate cyclase activity (Kebabian and Calne, 1979, Stoof and Kebabian, 1984).

Dopamine transporters (DAT) provide the re-uptake mechanism for terminating receptor stimulation by dopamine (Amara and Kuhar, 1993). DAT use energy of the electrochemical gradients of sodium and chloride to transport extracellular dopamine back into the neuron (Horn, 1990). Dopamine degradation is the other way to terminate the effect of dopamine. Dopamine can be degraded by two primary enzymes: catechol-O-methyltransferase (COMT, Axelrod et al., 1958, Axelrod, 1957) and monoamine oxidase (MAO, Rosengren, 1960). They metabolize dopamine to physiologically inactive metabolic products. MAO exists as two isozymes, A and B, with different substrate and inhibitor specificities. Dopamine is converted to 3-methoxytyramine by COMT and MAO converts dopamine to 3,4-dihydroxyphenylacetic acid (DOPAC, Rosengren, 1960). Homovanillic acid (HVA) is the main metabolite of dopamine (Goldstein et al., 1959) and is formed through subsequent degradation by COMT and MAO, in either order (see Fig. 2, Anden et al., 1963).

Every biochemical step in the neurotransmission and metabolism of dopamine corresponds to a specific enzyme, encoded for by a corresponding gene. Polymorphisms in these genes could have major implications for dopamine metabolism and neurotransmission and consequently cause neuropsychiatric disorders like MDD.

In this review, we focus on association studies between MDD and genes involved in the dopamine system. Association studies have a number of important limitations. First, most of the described studies have a small sample size leading to lack of statistical power to detect a small gene effect. A second important limitation of association studies is population stratification. A problem of population stratification is that significant differences are not due to disease status, but due to population differences between the two samples. With regard to drawing conclusions a review has also the limitation of publication bias. This concerns the fact that often studies which find no associations are less likely to be published. An additional limitation in association studies to MDD is the heterogeneity of MDD. MDD as phenotype might be too broad. Differences in findings between studies might be due to that these studies investigate different subtypes of MDD.

A method to overcome the first two limitations is meta-analysis. There are published meta-analyses on association studies between genes involved in dopamine processing and MDD (Lopez-Leon et al., 2005, Lopez-Leon et al., 2008). These meta-analyses have more power to detect small gene effects, but they do not extensively elaborate on how these genes may be involved in the susceptibility to MDD. In this review, we aim to give more structure to the current findings about the extent to which genes that code the above described steps of dopamine neurotransmission and metabolism influence the vulnerability to MDD and depressive symptoms. As MDD is a very heterogeneous disorder, we also discuss the involvement of genes on symptoms of MDD. These symptoms can also occur in other disorders, for example bipolar disorder. However, a full discussion of bipolar disorder is beyond the scope of our review, as we focus on MDD. The involvement of dopamine-related genes in bipolar disorder has already been reviewed elsewhere (Cousins et al., 2009). We will use MDD to refer to the diagnosis major depressive disorder and depression for other forms of depression, for example depression in patients with schizophrenia or bipolar disorder. Genes of dopamine anabolism, signalling and catabolism will be discussed, in that order. Table 2 provides an overview of published association studies.