Serotonin transporter occupancy of high-dose selective serotonin reuptake inhibitors during major depressive disorder measured with [11C]DASB positron emission tomography.

RATIONALE: Previous work has shown 80% serotonin transporter (5-HTT) occupancy to be a consistent finding at the minimum therapeutic dose during selective serotonin reuptake inhibitor (SSRI) treatment. [(11)C]N,N-dimethyl-2-(2-amino-4-cyanophenylthio) benzylamine positron emission tomography ([(11)C]DASB PET) is currently the best method available to quantify 5-HTT occupancy in humans. OBJECTIVES: The purpose of the present study is to determine 5-HTT occupancy during high dose SSRI treatment using [(11)C]DASB PET. MATERIALS AND METHODS: Twelve healthy subjects and 12 subjects with major depressive disorder completed the protocol. Depressed subjects received one [(11)C]DASB PET scan after a minimum of 4 weeks treatment at high doses of venlafaxine, sertraline, or citalopram. Baseline 5-HTT binding potential (BP) was taken as the average 5-HTT BP of the 12 healthy subjects. RESULTS: Mean striatal 5-HTT occupancy for each antidepressant group was approximately 85% at high therapeutic dose. This was significantly greater than 80% (one-sample t test; p < 0.04, venlafaxine group; p < 0.02, sertraline group; p < 0.01, citalopram group) for each high dose antidepressant group. CONCLUSIONS: Significantly greater 5-HTT blockade at high dose provides a rationale for raising the dose from the minimum therapeutic dose in specific clinical circumstances. It is likely that 15% unoccupied 5-HTT remains, which should be addressed in future drug development.

Novel 5-HTTLPR allele associates with higher serotonin transporter binding in putamen: a [(11)C] DASB positron emission tomography study.

BACKGROUND: The serotonin transporter (5-HTT)-linked polymorphic region (5-HTTLPR) has two frequent alleles, designated long (L), and short (S). The S allele is associated with lower levels of 5-HTT mRNA and lower 5-HTT expression in human cell lines. A functional single nucleotide variant was detected within L, designated L(A) and L(G). Only L(A) is associated with high levels of in vitro 5-HTT expression, whereas L(G) is low expressing and more similar to S. We examined the possible influence of the long (A/G) variant on 5-HTT density in the living human brain using 3-(11)C-amino-4-(2-dimethylaminomethylphenyl-sulfanyl) benzonitrile ([(11)C]DASB) positron emission tomography. METHODS: The 5-HTT binding potential (5-HTT BP), an index of 5-HTT density, was found in 43 healthy subjects genotyped for 5-HTTLPR long (A/G), and in an ethnically homogenous subsample of 30 Caucasian-Canadians. RESULTS: The L(A)/L(A) was associated with higher 5-HTT BP in putamen (p = .026, not corrected). This association became stronger in the Caucasian subsample (p = .004) and was significant even after correcting for multiple comparisons. CONCLUSIONS: The 5-HTTLPR long (A/G) polymorphism influences 5-HTT density leading to higher putamen 5-HTT BP in healthy L(A)/L(A) carriers of Caucasian ancestry. This finding extends the role of this polymorphism from in vitro reports of higher 5-HTT expression with the L(A)/L(A) genotype into in vivo brains of healthy human subjects.

Elevated monoamine oxidase a levels in the brain: an explanation for the monoamine imbalance of major depression.

CONTEXT: The monoamine theory of depression proposes that monoamine levels are lowered, but there is no explanation for how monoamine loss occurs. Monoamine oxidase A (MAO-A) is an enzyme that metabolizes monoamines, such as serotonin, norepinephrine, and dopamine. OBJECTIVE: To determine whether MAO-A levels in the brain are elevated during untreated depression. SETTING: Tertiary care psychiatric hospital. PATIENTS: Seventeen healthy and 17 depressed individuals with major depressive disorder that met entry criteria were recruited from the care of general practitioners and psychiatrists. All study participants were otherwise healthy and nonsmoking. Depressed individuals had been medication free for at least 5 months. MAIN OUTCOME MEASURE: Harmine labeled with carbon 11, a radioligand selective for MAO-A and positron emission tomography, was used to measure MAO-A DVS (specific distribution volume), an index of MAO-A density, in different brain regions (prefrontal cortex, anterior cingulate cortex, posterior cingulate cortex, caudate, putamen, thalamus, anterior temporal cortex, midbrain, hippocampus, and parahippocampus). RESULTS: The MAO-A DVS was highly significantly elevated in every brain region assessed (t test; P=.001 to 3x10(-7)). The MAO-A DVS was elevated on average by 34% (2 SDs) throughout the brain during major depression. CONCLUSIONS: The sizable magnitude of this finding and the absence of other compelling explanations for monoamine loss during major depressive episodes led to the conclusion that elevated MAO-A density is the primary monoamine-lowering process during major depression.

Elevated putamen D(2) receptor binding potential in major depression with motor retardation: an [11C]raclopride positron emission tomography study.

OBJECTIVE: Several antidepressants raise striatal dopamine, but the role of striatal dopamine during major depressive episodes is unclear. Striatal [(11)C]raclopride binding potential measured with positron emission tomography is an index of D(2) type receptors and is sensitive to extracellular dopamine levels (higher D(2) binding potential occurs when dopamine is lower). It was hypothesized that putamen D(2) binding potential would be higher during major depressive episodes featuring motor retardation. METHOD: Drug-free, nonsmoking subjects experiencing a major depressive episode (N=21) underwent [(11)C]raclopride PET imaging as did 21 healthy age-matched comparison subjects. Motor retardation was measured with the finger tapping test. RESULTS: The depressed subjects exhibiting motor retardation had significantly higher D(2) binding potential in both the left and right putamen than did healthy subjects, and putamen D(2) binding potential correlated significantly with motor speed in the depressed subjects. CONCLUSIONS: The results argue that extracellular dopamine is lower in subjects experiencing a major depressive episode that features motor retardation. This depression subtype should preferentially benefit from dopamine-increasing medications and should be targeted in future clinical trials of dopamine reuptake inhibitors.

Positron emission tomography quantification of [11C]-harmine binding to monoamine oxidase-A in the human brain.

This article describes the kinetic modeling of [(11)C]-harmine binding to monoamine oxidase A (MAO-A) binding sites in the human brain using positron emission tomography (PET). Positron emission tomography studies were performed in healthy volunteers at placebo conditions and after treatment with clinical doses of moclobemide. In either condition, a two-tissue compartment model (2CM) provided better fits to the data than a one-tissue model. Estimates of k(3)/k(4) values from an unconstrained 2CM were highly variable. In contrast, estimates of the specifically bound radioligand distribution volume (DV(B)) from an unconstrained 2CM were exceptionally stable, correlated well with the known distribution of MAO-A in the brain (cerebellum