Monoamine oxidase A inhibitor occupancy during treatment of major depressive episodes with moclobemide or St. John's wort: an [11C]-harmine PET study.

BACKGROUND: Monoamine oxidase A (MAO-A) inhibitor antidepressants raise levels of multiple monoamines, whereas the selective serotonin reuptake inhibitors (SSRIs) only raise extracellular serotonin. Despite this advantage of MAO-A inhibitors, there is much less frequent development of MAO inhibitors compared with SSRIs. We sought to measure brain MAO-A occupancy after 6 weeks of treatment in depressed patients with a clinically effective dose of a selective MAO-A inhibitor and measure MAO-A occupancy after repeated administration of St. John's wort, an herb purported to have MAO-A inhibitor properties. METHODS: Participants underwent 2 [(11)C]-harmine positron emission tomography scans. Healthy controls completed a test-retest condition, and depressed patients were scanned before and after repeated administration of moclobemide or St. John's wort for 6 weeks at the assigned dose. We measured MAO-A VT, an index of MAO-A density, in the prefrontal, anterior cingulate and anterior temporal cortices, putamen, thalamus, midbrain and hippocampus. RESULTS: We included 23 participants (10 controls and 13 patients with major depressive disorder [MDD]) in our study. Monoamine oxidase A VT decreased significantly throughout all regions after moclobemide treatment in patients with MDD compared with controls (repeated-measures analysis of variance, F1,15 = 71.08-130.06, p < 0.001 for all regions, mean occupancy 74% [standard deviation 6%]). Treatment with St. John's wort did not significantly alter MAO-A VT. LIMITATIONS: The occupancy estimates are limited by the sample size of each treatment group; hence, our estimate for the overall moclobemide occupancy of 74% has a 95% confidence interval of 70%-78%, and we can estimate with 95% certainty that the occupancy of St. John's wort is less than 5%. CONCLUSION: For new MAO-A inhibitors, about 74% occupancy at steady-state dosing is desirable. Consistent with this, St. John's wort should not be classified as an MAO-A inhibitor. The magnitude of MAO-A blockade during moclobemide treatment exceeds the elevation of MAO-A binding during illness by at least 30%, suggesting that the treatment effect should exceed the disease effect when designing selective antidepressants for this target.

Brain monoamine oxidase A binding in major depressive disorder: relationship to selective serotonin reuptake inhibitor treatment, recovery, and recurrence.

CONTEXT: Highly significant elevations in regional brain monoamine oxidase A (MAO-A) binding were recently reported during major depressive episodes (MDEs) of major depressive disorder (MDD). The relationship between MAO-A levels and selective serotonin reuptake inhibitor (SSRI) treatment, recovery, and recurrence in MDD is unknown. OBJECTIVES: To determine whether brain MAO-A binding changes after SSRI treatment, whether brain MAO-A binding normalizes in subjects with MDD in recovery, and whether there is a relationship between prefrontal and anterior cingulate cortex MAO-A binding in recovery and subsequent recurrence of MDE. DESIGN: Case-control study. SETTING: Tertiary care psychiatric hospital. PARTICIPANTS: Twenty-eight healthy subjects, 16 subjects with an MDE secondary to MDD, and 18 subjects with MDD in recovery underwent carbon 11-labeled harmine positron emission tomography scans. Subjects with MDE were scanned before and after 6 weeks of SSRI treatment. All were otherwise healthy, nonsmoking, and medication free. Subjects with MDD in recovery were followed up for 6 months after MAO-A binding measurement. MAIN OUTCOME MEASURE: Monoamine oxidase A V(T), an index of MAO-A density, was measured in the prefrontal cortex, anterior cingulate cortex, posterior cingulate cortex, dorsal putamen, ventral striatum, thalamus, anterior temporal cortex, midbrain, and hippocampus. RESULTS: Monoamine oxidase A V(T) was significantly elevated in each brain region both during MDE and after SSRI treatment as compared with healthy controls. During recovery, MAO-A V(T) was significantly elevated in each brain region; however, those who went on to recurrence had significantly higher MAO-A V(T) in the prefrontal and anterior cingulate cortex than those who did not. CONCLUSIONS: Elevated MAO-A binding after SSRI treatment indicates persistence of a monoamine-lowering process not present in health. This provides a strong conceptual rationale for continuing SSRI treatment during early remission. Greater MAO-A binding in the prefrontal and anterior cingulate cortex in subjects with MDD in recovery and its association with subsequent recurrence argue that deficient monoamine neuromodulation may persist into recovery and contribute to recurrence.

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.

Systemic obstacles to battered women's participation in the judicial system: when will the status quo change?

The Canadian government has introduced numerous policies, guidelines, and mandates at the federal and provincial levels that recognize woman abuse as a serious social problem and violation of the law. Nonetheless, recent feminist research continues to expose laws and practices that fail woman abuse victims. The present study examined the experiences of women victims in domestic violence cases and the barriers they faced in dealing with the police, the courts, and social service agencies. Despite government initiatives, the study results corroborate previous findings indicating that many battered women feel further traumatized by ambivalent or discriminatory attitudes and practices prevalent within the system.

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.

Brain serotonin transporter binding potential measured with carbon 11-labeled DASB positron emission tomography: effects of major depressive episodes and severity of dysfunctional attitudes.

BACKGROUND: Although brain serotonin transporter (5-HTT) density has been investigated in subjects with a history of major depressive episodes (MDE), there has never been an investigation of brain 5-HTT during a current MDE. Brain 5-HTT binding potential (BP) may have an important role during MDE due to major depressive disorder, because the 5-HTT regulates extracellular 5-HT. The BP is an index of receptor density. Carbon 11-labeled 3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile (DASB) positron emission tomography (PET) is the first brain imaging technique that can measure the 5-HTT BP in cortical and subcortical brain regions in vivo. The purposes of this study were to investigate 5-HTT BP during MDE and to determine the relationship between 5-HTT BP and negativistic dysfunctional attitudes during MDE. Dysfunctional attitudes are negatively biased assumptions and beliefs regarding oneself, the world, and the future. Our recent publication of increased serotonin2 BP in MDE with severely negativistic dysfunctional attitudes suggests that this subgroup of MDE subjects has very low levels of extracellular serotonin. METHODS: Regional 5-HTT BP was measured in 20 nonsmoking medication-free (> or =3 months) depressed subjects and 20 age-matched nonsmoking, medication-free, healthy subjects using [11C]DASB PET. Dysfunctional attitudes were measured using the Dysfunctional Attitudes Scale. RESULTS: No difference in regional 5-HTT BP was found between MDE and healthy subjects; however, the subgroup of MDE subjects with highly negativistic dysfunctional attitudes had significantly higher 5-HTT BP compared with healthy subjects in brain regions mainly sampling serotonergic nerve terminals (prefrontal cortex, anterior cingulate, thalamus, bilateral caudate, and bilateral putamen; average, 21% greater; F(1,26), 5.6-12.2 [P values, .03-.002]). In the MDE subjects, increased 5-HTT BP was strongly associated with more negativistic dysfunctional attitudes in brain regions primarily sampling serotonergic nerve terminals (prefrontal cortex, anterior cingulate, thalamus, caudate, and putamen; r = 0.64-0.74 [P values, .003 to <.001]). CONCLUSIONS: Serotonin transporters play an important role during depression. The magnitude of regional 5-HTT BP can provide a vulnerability to low levels of extracellular serotonin and symptoms of extremely negativistic dysfunctional attitudes.

Serotonin transporter occupancy of five selective serotonin reuptake inhibitors at different doses: an [11C]DASB positron emission tomography study.

OBJECTIVE: Minimum therapeutic doses of paroxetine and citalopram produce 80% occupancy for the serotonin (5-HT) transporter (5-HTT). The authors used [(11)C]DASB positron emission tomography to measure occupancies of three other selective serotonin reuptake inhibitors (SSRIs) at minimum therapeutic doses. The relationship between dose and occupancy was also investigated. METHOD: Striatal 5-HTT binding potential was measured in 77 subjects before and after 4 weeks of medication administration. Binding potential is proportional to the density of receptors not blocked by medication. Subjects received citalopram, fluoxetine, sertraline, paroxetine, or extended-release venlafaxine. Healthy subjects received subtherapeutic doses; subjects with mood and anxiety disorders received therapeutic doses. Percent reduction in 5-HTT binding potential for each medication and dose was calculated. To obtain test-retest data, binding potential was measured before and after 4 weeks in six additional healthy subjects. RESULTS: Substantial occupancy occurred at subtherapeutic doses for all SSRIs. Compared to test-retest data, each drug at the minimum therapeutic dose had a significant effect on striatal 5-HTT binding potential. Mean occupancy at this dose was 76%-85%. At higher plasma SSRI concentrations, 5-HTT occupancy tended to increase above 80%. For each drug, as the dose (or plasma level) increased, occupancy increased nonlinearly, with a plateau for higher doses. CONCLUSIONS: At tolerable doses, SSRIs have increasing occupancy with increasing plasma concentration or dose. Occupancy of 80% across five SSRIs occurs at minimum therapeutic doses. This suggests that 80% 5-HTT blockade is important for therapeutic effect. Occupancy should be measured during development of antidepressant compounds targeting the 5-HTT.