Jaana Kajander

Decreased brain serotonin 5-HT1A receptor availability in medication-naive patients with major depressive disorder: an in-vivo imaging study using PET and [carbonyl-11C]WAY-100635

Serotonin (5-HT) is involved in the pathophysiology of major depressive disorder (MDD). Among the numerous serotonergic receptors, the 5-HT1A receptor subtype is of interest because of its involvement in cognition, hippocampal neurogenesis, and mechanism of action of antidepressant drugs. Previous imaging studies have suggested altered availability of 5-HT1A receptors in MDD but prior antidepressant medication and chronicity of the illness may confound the interpretation. We examined 21 drug-naive primary-care patients with MDD using positron emission tomography (PET) imaging with [carbonyl-11C]WAY-100635, a radioligand for 5-HT1A receptors, along with 15 healthy control subjects. Binding to receptors was assessed both regionally and at voxel level with the binding potential (BP) that was estimated using arterial blood input. Compared with healthy controls, the BP of [carbonyl-11C]WAY-100635 was reduced in patients with MDD in most brain regions, ranging from -9% to -25%. Voxel-level analysis confirmed this finding by showing a widespread reduction of [carbonyl-11C]WAY-100635 BP. No statistically significant associations were observed between BP and total HAMD scores in the patients, but lower BP was associated with higher likelihood of insomnia. This study demonstrated a widespread reduction in the availability of serotonin 5-HT1A receptors in a relatively large sample of drug-naive primary-care patients with MDD, suggesting the involvement of this receptor subtype in the pathophysiology of the illness. Lack of correlation with overall severity of the illness may relate to a largely trait-like nature of this abnormality in depressive disorders.

The A1 allele of the human D2 dopamine receptor gene is associated with increased activity of striatal L-amino acid decarboxylase in healthy subjects.

The A1 allele of the TaqI restriction fragment length polymorphism (RFLP) of the human dopamine D2 receptor gene (DRD2) is associated with a low density of D2 dopamine receptors in the striatum. Because of the important role of D2 autoreceptors in regulating dopamine synthesis, we aimed to examine whether subjects with the A1 allele have altered presynaptic dopamine function in the brain. We also studied the effects of two other DRD2 polymorphisms, C957 T and −141C Ins/Del, which have been suggested to affect D2 receptor levels in brain. The relationships between the TaqIA RFLP, C957 T and −141C Ins/Del polymorphisms and striatal dopamine synthesis in 33 healthy Finnish volunteers were studied using positron emission tomography and [18F]fluorodopa ([18F]FDOPA), a radiolabelled analog of the dopamine precursor L-DOPA. Heterozygous carriers of the A1 allele (A1/A2; 10 subjects) had significantly higher (18%) [18F]FDOPA uptake in the putamen than subjects without the A1 allele (A2/A2; 23 subjects). C957 T and −141C Ins/Del polymorphisms did not significantly affect [18F]FDOPA Ki values. These results demonstrate that the A1 allele of DRD2 gene is associated with increased striatal activity of aromatic L-amino acid decarboxylase, the final enzyme in the biosynthesis of dopamine and the rate-limiting enzyme for trace amine (e.g. &bgr;-phenylethylamine) synthesis. The finding can be explained by lower D2 receptor expression leading to decreased autoreceptor function, and suggests that dopamine and/or trace amine synthesis rate is increased in the brains of A1 allele carriers.

Striatal Dopamine Synthesis in First-degree Relatives of Patients with Schizophrenia

BACKGROUND First degree relatives (FDR) of patients with schizophrenia have higher risk of developing schizophrenia than the general population. Previous positron emission tomography (PET) studies have shown that striatal presynaptic dopamine synthesis capacity is increased in schizophrenia. We investigated whether this same phenomenon is shared by individuals with increased genetic risk for schizophrenia. METHODS We used 6-[18F]-fluorodopa (FDOPA) PET imaging to measure striatal dopamine synthesis capacity. We studied 17 nonpsychotic subjects with an FDR with schizophrenia. This group was compared to 17 healthy subjects with no FDRs with schizophrenia. RESULTS A conventional region of interest (ROI)-analysis indicated that FDOPA uptake (K(i)) in the caudate-putamen was statistically significantly higher in the FDR group than in the control group. A voxel-level analysis confirmed these results. CONCLUSIONS These results suggest that the changes of striatal presynaptic dopamine synthesis seen previously in neuroleptic-naive schizophrenic patients is also present in FDRs of patients with schizophrenia. These findings have implications for the early detection of psychosis as well as for pharmacological interventions in individuals at risk for psychosis.

Cortical glutamate–dopamine interaction and ketamine-induced psychotic symptoms in man

RationaleThe noncompetitive glutamate N-methyl-d-aspartate receptor antagonist ketamine induces transient psychotic symptoms in man. Involvement of dopaminergic mechanisms in these effects has been suggested.ObjectivesThe purpose of this article is to study the effects of ketamine on extrastriatal dopamine receptor availability in healthy subjects and extracellular dopamine levels in rat cortex.Materials and methodsThe effect of computer-driven subanesthetic ketamine infusion on cortical dopamine release was studied in healthy male subjects using a controlled study design. Dopamine D2/D3 receptor availability was quantified using positron emission tomography (PET) and [11C]FLB 457. A conventional region of interest-based analysis and voxel-based analysis was applied to the PET data. The ketamine-induced cortical dopamine release in rats was studied using in vivo microdialysis.ResultsKetamine infusion reduced significantly the [11C]FLB 457 binding potential (BP) in the posterior cingulate/retrosplenial cortices, suggestive of increased dopamine release. This brain imaging finding was further supported by a microdialysis experiment in rats showing that ketamine increased the extracellular dopamine concentration by up to 200% in the retrosplenial cortex. Ketamine-induced psychotic symptoms were associated with changes in the [11C]FLB 457 BP in the dorsolateral prefrontal and anterior cingulate cortices.ConclusionsOur results suggest that cortical dopaminergic mechanisms have a role in the emergence of ketamine-induced psychosis-like symptoms in man. The glutamate–dopamine interaction in the posterior cingulate during ketamine infusion is well in line with the recent functional and structural imaging studies suggesting involvement of this cortical area in the development of schizophrenic psychosis.

Brain serotonin 1A receptor binding in bulimia nervosa.

BACKGROUND Selective serotonin reuptake inhibitors (SSRIs) are the first choice for the pharmacologic treatment of bulimia nervosa, but there are no published data on the putative altered serotonin (5-HT) receptor characteristics in patients with bulimia. Experimental studies suggest that the therapeutic antidepressant effect of SSRIs is mediated via 5-HT(1A) receptors. The aim of this study was to measure brain 5-HT(1A) receptor binding among nonmedicated patients with bulimia nervosa. METHODS Positron emission tomography (PET) with a selective 5-HT(1A) ligand, [11C]WAY-100635, was performed on eight unmedicated patients with bulimia and 10 healthy comparison subjects. RESULTS The binding potential values were greater in patients than in control subjects in all brain regions studied. The most robust differences were observed in the angular gyrus, the medial prefrontal cortex, and the posterior cingulate cortex. CONCLUSIONS These results suggest that brain 5-HT(1A) receptor binding is increased in several cortical areas in patients with bulimia nervosa during their state of impulsive binge eating.

Short-Term Psychodynamic Psychotherapy and Fluoxetine in Major Depressive Disorder: A Randomized Comparative Study

Background: There are few studies comparing the efficacy of short-term psychodynamic psychotherapy (STPP) and pharmacotherapy in major depressive disorder. We conducted a comparative study on the efficacy of STPP versus fluoxetine treatment in patients with major depressive disorder in a primary care setting. Methods: Fifty-one patients with major depressive disorder (DSM-IV) of mild or moderate severity were recruited through occupational health services providing primary health care. Patients were randomized to receive either STPP (1 session/week) or fluoxetine treatment (20–40 mg/day) for 16 weeks. The outcome measures included the Hamilton Depression Rating Scale (HDRS), the Beck Depression Inventory (BDI), and the Social and Occupational Functioning Assessment Scale (SOFAS). Results: Intent-to-treat analyses indicated that both treatments were highly effective in reducing the HDRS (p < 0.0001) and BDI (p < 0.0001) scores, as well as in improving functional ability (SOFAS; p < 0.0001), with no statistically significant differences between the treatments. Of those 40 subjects who completed the follow-up, 57% in the psychotherapy group and 68% in the fluoxetine group showed full remission (HDRS ≤7) after 4 months. Conclusions: Both STPP and pharmacological treatment with fluoxetine are effective in reducing symptoms and in improving functional ability of primary care patients with mild or moderate depression. This study suggests no marked differences in the therapeutic effects of these two treatment forms in a primary care setting.

Measurement of Serotonin 5-HT1A Receptor Binding Using Positron Emission Tomography and [carbonyl-11C]WAY-100635—Considerations on the Validity of Cerebellum as a Reference Region

[Carbonyl-11C]WAY-100635 has been used extensively in positron emission tomography (PET) imaging of serotonin 1A receptors (5-HT1A) in vivo in the human brain. Specific binding to receptors is usually estimated using compartmental modeling with arterial plasma input function. The use of reference tissue input (cerebellum) enables quantification without the need of arterial blood sampling, but the accuracy of this method is highly dependent on the validity of the reference region in terms of both specific and nonspecific binding. In this paper, we report exceptionally high uptake of [carbonyl-11C]WAY-100635 in the gray matter of cerebellum in one healthy male subject, which was reproducible in repeated PET scanning and most likely represents specific binding to 5-HT1A receptors in cerebellar gray matter. Serotonin 1A receptors are transiently expressed in the human cerebellum during early childhood and usually level off until adolescence but may persist in some individuals. As a methodological implication, the results of this study with regard to test–retest characteristics of [carbonyl-11C]WAY-100635 measurements in healthy volunteers using both arterial plasma and reference tissue input functions support the use of cerebellar white matter as reference region, to avoid the potential bias originating from binding of [carbonyl-11C]WAY-100635 to 5-HT1A receptors in cerebellar gray matter.

Research Letter:Psychotherapy increases brain serotonin 5-HT1A receptors in patients with major depressive disorder

The serotonin 5-HT1A receptor system is implicated in the pathophysiology of major depressive disorder (MDD) (Stockmeier, 2003) and serotonergic medications are currently widely used in the treatment of MDD. Previous molecular imaging studies in patients with MDD have provided evidence of a widespread decrease in the density of serotonin 5-HT1A receptors in the disease (Drevets et al. 1999; Sargent et al. 2000 ; Bhagwagar et al. 2004 ; Meltzer et al. 2004 ; Hirvonen et al. 2008, but see Parsey et al. 2006 for opposite results). Psychotherapy usually results in clinically identical outcomes with medication in the treatment of patients with mild to moderate MDD (Ebmeier et al. 2006). However, nothing is known about the molecular mechanisms mediating the effects of psychotherapy. To test and compare the effects of fluoxetine medication and a brief psychotherapy on 5-HT1A receptor density in patients with MDD we conducted a randomized comparative study. Positron emission tomography (PET) scanning with the 5-HT1A radiotracer [carbonyl-C]WAY-100635 was performed before and after the intervention to measure alterations in 5-HT1A receptor binding.

Alfentanil increases cortical dopamine D2/D3 receptor binding in healthy subjects.

&NA; Animal studies have shown that opioids modulate the function of dopaminergic neurons. The effect of alfentanil on cortical and thalamic binding of the D2/D3 receptor ligand [11C]FLB 457 was evaluated in eight healthy subjects with positron emission tomography. The simplified reference tissue model was used to calculate tracer binding potential (BP) during a baseline condition and target‐controlled infusion of alfentanil, and the results were analyzed using a comparison group not receiving opioid. Behavioral and analgesic effects of alfentanil were also evaluated. In the region‐of‐interest analysis, alfentanil increased the BP of [11C]FLB 457 in the medial frontal cortex (P=0.028), dorsolateral prefrontal cortex (P=0.027), superior temporal cortex (P=0.028), and medial thalamus (P=0.003). These results were confirmed in a voxel‐based analysis, which further revealed an opioid‐induced increase in [11C]FLB 457 BP in the anterior cingulate cortex (P<0.001). Alfentanil induced euphoria (P=0.03) and analgesia (P=0.006). Cheerfulness (r=0.982, P<0.001) and euphoria (r=0.918, P=0.001) were associated with increased BP of [11C]FLB 457 in the left posterior cingulate cortex, but the analgesic effect of alfentanil did not correlate with changes in [11C]FLB 457 BP. The results of this study demonstrate opioid–dopamine interactions in frontal and temporal cortical regions and the thalamus in healthy subjects. Increased D2/D3 tracer binding during opioid infusion may reflect decreased synaptic dopamine levels. The association of the uplifting effect of alfentanil with increased D2/D3 binding in the posterior cingulate cortex suggests that cortical dopamine may be involved in the behavioral effects of opioids.

Striatal dopamine D2 receptors in medication-naive patients with major depressive disorder as assessed with [11C]raclopride PET

RationaleAmong other monoamine neurotransmitters, dopamine is implicated in the pathophysiology of major depression. Experimental studies suggest the involvement of the mesolimbic dopamine system in the mechanism of action of antidepressant drugs. Previous in vivo imaging studies have studied striatal dopamine D2 receptor availability in depression but the results are equivocal thus far.ObjectiveTo study the striatal and thalamic dopamine D2 receptor availability in drug-naive patients with major depression was the aim of this study.Materials and methodsCaudate, putamen, and thalamic dopamine D2 receptor availability was estimated using positron emission tomography and [11C]raclopride in 25 treatment-seeking drug-free patients (of whom 24 were drug-naive) with major depression (primary care patients) as well as in 19 demographically similar healthy control subjects. Receptor availability was expressed as the binding potential (BPND), and analyses were carried out based on both regional and voxel-level BPND estimates.ResultsNo statistically significant differences in [11C]raclopride BPND were observed between the groups either in the caudate nucleus (+1.7%, CI −4.8% to +8.3%), putamen (−1.0%, CI −7.2% to 5.1%), thalamus (−2.4%, CI −8.7% to 4.0%), or ventral striatum (−3.8%, CI −9.3% to +1.6%). In the patients, depressive symptoms were not associated with [11C]raclopride BPND in any region.ConclusionsThe findings in this sample of treatment-seeking, drug-naive and predominantly first-episode patients with major depression do not support the involvement of striatal dopamine D2 receptors in the pathophysiology of the illness, but do not exclude the potential importance of dopaminergic mechanisms in antidepressant drug action.