symptoms as continuous variables may increase the power to detect associations with genetic polymorphisms. However, few studies have so far investigated an association of the 5-HTTLPR with the symptomatic profile and symptom severity of PD patients in terms of continuous variables. While no association was found in korean panic patients
198, we report a linear relationship with the 5-HTTLPR s-allele and symptoms of panic and depression in a sample of swedish PD patients (see Study III).
Additionally, the 5-HTTLPR has been associated with the outcome of pharmacological treatment in various psychiatric populations. Pharmacogenetic studies have linked the 5-HTTLPR l/l genotype to better efficacy of SSRI treatment in depression 205 as well as in different cohorts of unipolar, bipolar and psychotic depression patients 139. Very recently, a study in PTSD patients provided preliminary evidence that 5-HTTLPR s-carriers may not only profil less from pharmacological treatment but also may profit less from CBT 108.
Few studies have investigated the role of 5-HTTLPR in the outcome of pharmacological treatment in PD. While no association was found in a korean sample
198, the l-allele was associated with better treatment response to paroxetine females italians 206.
1.6.2 Dopamine synthesis and turnover
DA is a member of the catecholamine family and is a precursor to norepinephrine (noradrenaline) and epinephrine (adrenaline) in the biosynthetic pathway. In DAergic neurons, DA is synthesized from the amino acid tyrosine, which is able to pass the blood-brain barrier. In catecholamine neurons, tyrosine is converted into L-3,4-dihydroxyphenylalanine (L-DOPA) by the enzyme thyrosine hydroxylase (TH), which is the rate limiting step in DA synthesis. L-DOPA is then converted by L-amino acid decarboxylase (AADC) to DA.
After synthesis, DA is packed into vesicles which are then released into the synaptic cleft in response to a presynaptic action potential. Subsequently, DA binds to its receptors on the postsynaptic or the presynaptic neuron. DA receptors belong to five different receptor subtypes, labeled D1-D5, which can be classified into the D1-subtype (D1-R, D5-R) or the D2-subtype (D2-R, D3-R, D5R) 212.
The termination of DA signaling is achieved by two major mechanisms: reuptake into the presynapse by the dopamine transporter (DAT) or by enzymatic breakdown by the enzymes catechol-O-methyltransferase (COMT) and MAO-A.
Because a genetic polymorphism in the gene coding for the enzyme COMT was studied in Study I, IV, and V, the next chapter describes the functions of COMT and its val158met polymorphism in more detail.
1.6.2.1 Catechol-O-methyltransferase
Catechol-O-methyltransferase (COMT) was discovered in 1957 by Julius Axelrod 213 and is an one out of several enzymes that degrade catecholamines such as DA, norepinephrine and epinephrine. COMT introduces a methyl group to the catecholamine, which leads to inactivation of catecholamine neurotransmitters 214, and converts dopamine to inactive 3-methoxytyramine (3-MT). Two COMT protein isoforms are known: The soluble cytoplasmic isoform (S-COMT) is the predominant form in most tissues 215 while a longer, membrane-bound form (MB-COMT) is the major form expressed in the brain 216.
Despite the fact, that reuptake by the DAT is the primary mechanism for removing extracellular DA, enzymatic degradation by COMT is particularly important in brain areas devoid of DAT e.g. the prefrontal cortex 216, as opposed to DAT rich areas like the striatum. This is supported by studies in COMT knockout mice that provided evidence for increased DA levels in frontal areas while no effect was observed on DA levels in the striatum. Furthermore, in the frontal cortex, COMT seems to have a major impact selectively on DA levels but not on other catecholamine levels which may be due to the presence of noradrenalin transporters in this brain region 214.
In the brain, the hippocampus and the PFC show the most abundant expression of COMT mRNA while it is basically absent in the amygdala 217.
In general, females express lower levels of COMT 218, 219 due to an inhibitory effect of estrogen on COMT gene transcription 220. Human studies often, but not always, report female specific genotype effects 221, probably due to significantly lower COMT activity and possibly because COMT activity may have to fall below a specific threshold to yield associations.
1.6.3 The COMT gene and its val158met polymorphism
The COMT gene, located on 22q11.1 – q11.2, harbors an interesting and widely studied functional AG SNP that leads to the substitution of the amino acid valine by methionine at codon 158 of MB-COMT (COMTval158met, rs4680 previously rs165688), and codon 108 of S-COMT. The COMT val158met SNP is human specific and evolutionary recent 222.
Both the valine (val) and the methionine (met) allele have a frequency of about 50%
in caucasian populations but frequencies differ widely between geographical regions and ethnical groups 222.
The COMTval158met SNP affects the stability of the COMT protein at body temperature. The more stable val-variant has been shown to have a four times higher enzymatic activity as compared to the met-variant and thus lower extracellular DA levels 223. Therefore, the val-allele is sometimes also referred to as the high activity (H) allele while the met-allele is referred to as the low activity (L) allele. Both alleles seem to act in a co-dominant way, leading to a trimodal distribution of COMT activity in human populations 224. The COMTval158met SNP affects the effectiveness of DA degradation by COMT (primarily in the PFC, see 1.6.2.1) and thereby the availability of synaptic DA after neurotransmitter release and the stimulation of post-synaptic DA receptors.
1.6.4 Association studies of the COMTval158met
As enzymatic brake-down by COMT is the major way of dopamine degradation in prefrontal areas, the functional COMTval158met polymorphism has the potential to affect functions relying heavily on frontal cortex involvement such as the top-down regulation of emotion and executive control functions. There is also considerable evidence for gender specific effects of the COMTval158met polymorphism 225.
In the following sections, the relevant literature on behavioral, imaging and psychiatric genetics will be summarized, focusing on human data.
Behavioral Genetics
The association of the COMTval158met met-allele with better cognitive functions (in particular executive functions and working memory) is the best known association of the COMTval158met polymorphism with behavioral phenotypes 226, 227, even though a recent meta-analysis did not confirm this association 228.
There is also evidence for an effect of COMTval158met on affect modulation and emotional processing. Individuals with the met/met genotype have been shown to display increased affective startle modulation to aversive pictures (as opposed to startle probe alone) 229.
Additionally, the met-allele has been associated with increased maintenance and impaired flexibility 230, which may ultimately lead to emotional preservation and behavioural rigidity (as seen in anxiety and depression). The val-allele in turn has been associated with increased proneness to overcome a dominant response but impaired cognitive stability, which may lead to distractibility and impulsiveness (as seen e.g. in schizophrenia) 231.
Imaging Genetics
Like behavioral genetic studies have associations of the COMTval158met polymorphism with executive functions and emotional processing been found in imaging genetics studies.
The COMTval158met polymorphism has consistently been associated with human cognition, executive functions and frontal lobe functioning 214. Specifically, the met-allele is associated with better performance and a more focused physiological response in the ventrolateral (vl) PFC as measured by fMRI 214, 232.
Furthermore, met-carriers demonstrate increased activation in limbic areas (e.g.
amygdala, hippocampus and thalamus) and connected prefrontal brain regions (e.g.
vlPFC) during the processing of unpleasant stimuli (e.g. aversive pictures, faces displaying negative emotions) using fMRI 233, 234. Individuals with the met/met genotype also responded more sensitively to unpleasant stimuli using EEG 235.
Is has been suggested, that the signaling of emotional salience may be enhanced in individuals with the COMT met-allele 221. The impact of the COMTval18met polymorphism on amygdala activation (see above) may, as shown in animal studies, be explained by its modulatory effect on prefrontal DA levels. DA has been shown to potentiate the response of the amygdala by attenuating the effect of inhibitory input from the prefrontal cortex and augmenting the effect of excitatory input from sensory cortices 236.
Psychiatric Genetics focusing on PD and pharmacogenetics
Most studies investigating an association between the COMTval158met polymorphism and PD have used a case-control design and yielded contradictory findings.
The val-allele has been shown to be more frequent in female german 237, canadian 238 as well as mixed caucasian PD patients 239, while the met-allele has been shown to be overrepresented in korean PD patients 240, 241 and no association was found in japanese patients 242. A recent metaanalysis 243 thus concluded, that the val-allele may be associated with an increased risk of PD in caucasians while in asian populations the met-allele may be the risk allele.
Little research has been done on the association of the COMTval158met polymorphism and panic related endophenotypes like treatment outcome or the symptomatic profile. Two studies in korean PD patients associate the met/met genotype with poor improvement after pharmacological treatment with paroxetine 240, 241 but no studies in caucasians have been reported so far.
Furthermore, treatment outcome to various other types of treatment in different psychiatric populations has also been associated to the COMTval158met polymorphism. In depressive patients, the COMT val/val genotype was associated with a positive response to electroconvulsive therapy 244 and a better response to pharmacological treatment with mitrazapine but not paroxetine 245 while patients with the met/met genotype had an increased risk of nonremission after treatment with SSRI
246. Similarly, schizophrenic patients with the met/met genotype required higher doses of antipsychotic medication to achieve a significant reduction in psychotic symptoms
247. Additionally, in Study IV, we report preliminary evidence that PD patients with the
met/met genoptye seem to profit less from exposure-based CBT treatment than val-carriers.
It is possible, that patients with the met/met genotype may be generally less responsive to treatment as compared to non-carriers irrespective of the underlying disease.