raclopride and Depressive-Disorder--Major

Option generation is a critical process in decision making, but previous studies have largely focused on choices between options given by a researcher. Consequently, how we self-generate options for behaviour remain poorly understood. Here, we investigated option generation in major depressive disorder and how dopamine might modulate this process, as well as the effects of modafinil (a putative cognitive enhancer) on option generation in healthy individuals. We first compared differences in self-generated options between healthy non-depressed adults [n = 44, age = 26.3 years (SD 5.9)] and patients with major depressive disorder [n = 54, age = 24.8 years (SD 7.4)]. In the second study, a subset of depressed individuals [n = 22, age = 25.6 years (SD 7.8)] underwent PET scans with 11C-raclopride to examine the relationships between dopamine D2/D3 receptor availability and individual differences in option generation. Finally, a randomized, double-blind, placebo-controlled, three-way crossover study of modafinil (100 mg and 200 mg), was conducted in an independent sample of healthy people [n = 19, age = 23.2 years (SD 4.8)] to compare option generation under different doses of this drug. The first study revealed that patients with major depressive disorder produced significantly fewer options [t(96) = 2.68, P = 0.009, Cohen's d = 0.54], albeit with greater uniqueness [t(96) = -2.54, P = 0.01, Cohen's d = 0.52], on the option generation task compared to healthy controls. In the second study, we found that 11C-raclopride binding potential in the putamen was negatively correlated with fluency (r = -0.69, P = 0.001) but positively associated with uniqueness (r = 0.59, P = 0.007). Hence, depressed individuals with higher densities of unoccupied putamen D2/D3 receptors in the putamen generated fewer but more unique options, whereas patients with lower D2/D3 receptor availability were likely to produce a larger number of similar options. Finally, healthy participants were less unique [F(2,36) = 3.32, P = 0.048, partial η2 = 0.16] and diverse [F(2,36) = 4.31, P = 0.021, partial η2 = 0.19] after taking 200 mg versus 100 mg and 0 mg of modafinil, while fluency increased linearly with dosage at a trend level [F(1,18) = 4.11, P = 0.058, partial η2 = 0.19]. Our results show, for the first time, that option generation is affected in clinical depression and that dopaminergic activity in the putamen of patients with major depressive disorder may play a key role in the self-ge

Topics: Adult; Cross-Over Studies; Depression; Depressive Disorder, Major; Dopamine; Humans; Modafinil; Positron-Emission Tomography; Raclopride; Receptors, Dopamine D3; Young Adult

A high-risk subgroup of older patients with depression has slowed processing and gait speeds. This study examined whether carbidopa/levodopa (L-DOPA) monotherapy increased dopamine availability, increased processing/gait speed, and relieved depressive symptoms.. Adult outpatients with depression >59 years old underwent baseline [. Thirty-six subjects participated (age, 75.3 ± 7.5 years; 44.4% male). Significant, dose-dependent increases in processing and gait speed were observed with L-DOPA (450-mg dose: processing speed factor score effect size = 0.41, p = .001; dual-task gait speed effect size = 0.43, p = .002). [. By enhancing availability of dopamine, L-DOPA improved processing and gait speed in older adults with depression and significantly decreased [

Topics: Aged; Aged, 80 and over; Carbidopa; Corpus Striatum; Depressive Disorder, Major; Dopamine; Dopamine Antagonists; Drug Combinations; Female; Humans; Levodopa; Magnetic Resonance Imaging; Male; Middle Aged; New York; Positron-Emission Tomography; Raclopride; Receptors, Dopamine D2; Walking Speed

Antidepressant drug treatment and psychotherapy are both effective in treating major depression, but there are no published studies comparing the effects of these two treatments on the dopaminergic neurotransmitter system in major depression. We conducted a randomized comparative study on the effects of fluoxetine medication and short-term psychodynamic psychotherapy on striatal and thalamic dopamine D(2/3) receptors in patients with major depression. Duration of the treatment was 4 months, and dopamine D(2/3) receptor binding was quantified before and after treatment as the binding potential (BP (ND)) using [(11)C]raclopride and 3D positron emission tomography. Both treatments were clinically effective in treating major depression, as shown by substantial decreases in symptom ratings. Yet, there were no effects on D(2/3) receptor availability in the ventral striatum or other subdivisions of the striatum. Fluoxetine but not psychotherapy increased [(11)C]raclopride BP (ND) in lateral thalamus (+7.74%, p = 0.002) but this increase was not correlated with clinical improvement. In conclusion, this preliminary study does not support the involvement of ventral dopaminergic neurotransmission in the antidepressant effects of fluoxetine or psychodynamic psychotherapy. The effects of fluoxetine on thalamic dopamine systems need to be further explored.

Topics: Adult; Antidepressive Agents, Second-Generation; Carbon Radioisotopes; Corpus Striatum; Depressive Disorder, Major; Female; Fluoxetine; Humans; Male; Middle Aged; Positron-Emission Tomography; Psychotherapy; Raclopride; Receptors, Dopamine D2; Receptors, Dopamine D3; Thalamus

Anhedonia is hypothesized to be associated with blunted mesocorticolimbic dopamine (DA) functioning in samples with major depressive disorder. The purpose of this study was to examine linkages between striatal DA, reward circuitry functioning, anhedonia, and, in an exploratory fashion, self-reported stress, in a transdiagnostic anhedonic sample.. Relative to controls, the anhedonia group exhibited decreased task-related DA release in the left putamen, caudate, and nucleus accumbens and right putamen and pallidum. There were no group differences in task-related brain activation (fMRI) during reward processing after correcting for multiple comparisons. General functional connectivity (GFC) findings revealed blunted fMRI connectivity between PET-derived striatal seeds and target regions in the anhedonia group. Associations were identified between anhedonia severity and the magnitude of task-related DA release to rewards in the left putamen, but not mesocorticolimbic GFC.. Results provide evidence for reduced striatal DA functioning during reward processing and blunted mesocorticolimbic network functional connectivity in a transdiagnostic sample with clinically significant anhedonia.

Topics: Anhedonia; Depressive Disorder, Major; Dopamine; Humans; Magnetic Resonance Imaging; Positron-Emission Tomography; Raclopride

Major depressive disorder (MDD) is characterized by the altered integration of reward histories and reduced responding of the striatum. We have posited that this reduced striatal activation in MDD is due to tonically decreased stimulation of striatal dopamine synapses which results in decremented propagation of information along the cortico-striatal-pallido-thalamic (CSPT) spiral. In the present investigation, we tested predictions of this formulation by conducting concurrent functional magnetic resonance imaging (fMRI) and

Topics: Adult; Brain Mapping; Corpus Striatum; Depressive Disorder, Major; Dopamine; Female; Humans; Magnetic Resonance Imaging; Male; Neural Pathways; Positron-Emission Tomography; Raclopride

The A1 allele of the DRD2/ANKK1 Taq1A polymorphism (rs1800497) is associated with reduced striatal D(2/3) receptor binding in healthy individuals (Con) as well as depression and addiction. However, the effect of rs1800497 on D(2/3) receptor binding in depressed patients as well as the SNP's effect on D(2/3) binding during reward-associated dopamine release is unknown. Twelve unmedicated patients with major depressive disorder (MDD) and 24 Con completed PET scans with [(11)C]raclopride, once without receiving monetary rewards (baseline) and once while winning money. In Con, the A1 allele was associated with reduced baseline binding potential (BP(ND)) in the middle caudate and ventral striatum. However, in MDD patients the A1 allele was associated with increased baseline BP(ND) in these regions. There were no significant associations between rs1800497 and change in BP(ND) during reward-associated dopamine release. Conceivably, the A1 allele predisposes to depression and addiction via its effect on the post-synaptic D(2) receptor.

Topics: Adult; Brain; Case-Control Studies; Depressive Disorder, Major; Dopamine Antagonists; Female; Gambling; Genotype; Humans; Male; Middle Aged; Phenotype; Polymorphism, Single Nucleotide; Positron-Emission Tomography; Raclopride; Receptors, Dopamine D2; Receptors, Dopamine D3; Reward

Abnormalities of motivation and behavior in the context of reward are a fundamental component of addiction and mood disorders. Here we test the effect of a functional missense mutation in the dopamine 3 receptor (DRD3) gene (ser9gly, rs6280) on reward-associated dopamine (DA) release in the striatum. Twenty-six healthy controls (HCs) and 10 unmedicated subjects with major depressive disorder (MDD) completed two positron emission tomography (PET) scans with [(11)C]raclopride using the bolus plus constant infusion method. On one occasion subjects completed a sensorimotor task (control condition) and on another occasion subjects completed a gambling task (reward condition). A linear regression analysis controlling for age, sex, diagnosis, and self-reported anhedonia indicated that during receipt of unpredictable monetary reward the glycine allele was associated with a greater reduction in D2/3 receptor binding (i.e., increased reward-related DA release) in the middle (anterior) caudate (p<0.01) and the ventral striatum (p<0.05). The possible functional effect of the ser9gly polymorphism on DA release is consistent with previous work demonstrating that the glycine allele yields D3 autoreceptors that have a higher affinity for DA and display more robust intracellular signaling. Preclinical evidence indicates that chronic stress and aversive stimulation induce activation of the DA system, raising the possibility that the glycine allele, by virtue of its facilitatory effect on striatal DA release, increases susceptibility to hyperdopaminergic responses that have previously been associated with stress, addiction, and psychosis.

Topics: Adult; Age Factors; Alleles; Anhedonia; Basal Ganglia; Case-Control Studies; Caudate Nucleus; Depressive Disorder, Major; Dopamine D2 Receptor Antagonists; Female; Gambling; Humans; Male; Middle Aged; Motivation; Polymorphism, Genetic; Positron-Emission Tomography; Raclopride; Receptors, Dopamine D2; Receptors, Dopamine D3; Reward; Sex Factors

Dopamine (DA) system dysfunction is implicated in the pathophysiology of major depressive disorder (MDD). We sought to determine if cigarette smokers with a history of MDD and current mild depressive symptoms have abnormal smoking-induced DA release (measured indirectly as change in (11)C-raclopride binding potential [BP(ND)]).. Fifty-six cigarette smokers either with (n = 10) or without (n = 46) a history of MDD (MDD+ and MDD-, respectively) underwent bolus-plus-continuous-infusion (11)C-raclopride positron emission tomography, during which they smoked a regular cigarette. Presmoking to postsmoking changes in (11)C-raclopride BP(ND) were compared between groups. Also, correlations were determined between change in BP(ND) and depression, anxiety, and withdrawal rating scale scores for the MDD+ group.. The MDD+ group had a significantly greater reduction in (11)C-raclopride BP(ND) (-16.3%) than the MDD- group (-8.4%) (analysis of covariance [ANCOVA], p = .03). Significant negative correlations were found between depression/anxiety and change in (11)C-raclopride BP(ND) (r = -.77, p < .01 and r = -.74, p = .01, respectively).. MDD+ smokers have greater smoking-induced DA release than MDD- smokers, and higher depression/anxiety levels are associated with greater smoking-induced DA release. These findings support the theory that MDD+ smokers have DA system dysfunction, including heightened smoking-induced DA release.

Topics: Adult; Aged; Anxiety; Brain; Depressive Disorder, Major; Dopamine; Female; Humans; Male; Middle Aged; Positron-Emission Tomography; Raclopride; Radioligand Assay; Smoking; Substance Withdrawal Syndrome; Tobacco Use Disorder

Among 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.. To study the striatal and thalamic dopamine D2 receptor availability in drug-naive patients with major depression was the aim of this study.. Caudate, 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 (BP ND), and analyses were carried out based on both regional and voxel-level BP ND estimates.. No statistically significant differences in [11C]raclopride BP ND 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 BP ND in any region.. The 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.

Topics: Adult; Brain Mapping; Carbon Radioisotopes; Corpus Striatum; Depressive Disorder, Major; Dominance, Cerebral; Dopamine Antagonists; Female; Humans; Male; Middle Aged; Positron-Emission Tomography; Raclopride; Receptors, Dopamine D2; Reference Values; Thalamus

Reduced dopaminergic function may occur in depressive disorders. In this paper the results of two pilot studies examining different aspects of the dopamine system in depression are presented. First, the binding of [(11)C]FLB 457 to extrastriatal D(2) receptors was measured in a group of depressed patients. Second, the hypothesis that selective serotonin reuptake inhibiting (SSRI) antidepressants affect the striatal binding of [(11)C]raclopride was tested.. In the first study the binding of [(11)C]FLB 457 was compared between 7 people with depression and 7 healthy controls. In the second study the binding of [(11)C]raclopride to striatal D(2/3) receptors was compared between 8 people taking SSRI antidepressant medication and 8 healthy controls.. There was no difference in the binding of [(11)C]FLB 457 between the two groups. [(11)C]raclopride binding was reduced in the dorsal striatum of people taking antidepressants suggesting either that D(2/3) expression was reduced, or that dopamine release was increased, compared to untreated controls.. The depressed patients were not severely depressed and were not matched for gender with controls. In the raclopride group the patients and controls were not matched by gender and were taking different SSRI antidepressants.. We found no support for the hypothesis that dopamine D(2) receptor expression is altered in extrastriatal brain regions in depression. SSRI antidepressants were associated with reduced [(11)C]raclopride binding in the dorsal striatum supporting the hypothesis that therapeutic effects of such drugs may, in part, be due to changes in the dopamine system.

Topics: Adult; Brain; Brain Mapping; Carbon Radioisotopes; Corpus Striatum; Depressive Disorder, Major; Dopamine Antagonists; Female; Humans; Image Processing, Computer-Assisted; Male; Middle Aged; Motivation; Pilot Projects; Positron-Emission Tomography; Pyrrolidines; Raclopride; Radioligand Assay; Receptors, Dopamine D2; Reference Values; Salicylamides; Selective Serotonin Reuptake Inhibitors

Several studies have demonstrated that repetitive transcranial magnetic stimulation (rTMS) elicits moderate antidepressant effects. Several previous studies suggested that the dopaminergic system might be related to this therapeutic action of rTMS. We attempted to determine the effects of chronic rTMS on central dopaminergic function in depression using positron emission tomography (PET) with [11C]raclopride.. Nine patients with depression were treated with 10 daily sessions of rTMS (10 Hz, 5 s train, 20 trains at 100% motor threshold per session) over the left dorsolateral prefrontal cortex (DLPFC). Each patient underwent two [11C]raclopride PET scans and neuropsychological tests - before rTMS and 1 day after rTMS.. In five patients, the Hamilton Rating Scale for Depression (HRSD) significantly decreased. Patients showed significant improvement in verbal memory following rTMS. There were no changes in [11C]raclopride binding in the caudate nucleus and putamen after rTMS treatment.. Our sample size was limited, and our study was an open trial lacking sham-treated controls.. This study suggests that rTMS may be effective for the treatment of depression and also may improve verbal memory function. We observed no changes in [11C]raclopride binding, suggesting that there was no measurable increase in the release of dopamine at the second PET scan. Several animal studies and healthy human studies have indicated that dopamine can be released soon after acute rTMS. Our results suggest that release of striatal dopamine induced by rTMS may be only transient, or that dopamine release may be attenuated following chronic rTMS.

Topics: Adult; Antidepressive Agents, Second-Generation; Cognition; Depressive Disorder, Major; Dopamine; Dopamine Antagonists; Female; Fluvoxamine; Humans; Male; Neuropsychological Tests; Positron-Emission Tomography; Raclopride; Severity of Illness Index; Transcranial Magnetic Stimulation

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.. 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.. 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.. 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.

Topics: Adult; Age Factors; Carbon Radioisotopes; Corpus Striatum; Depressive Disorder, Major; Dopamine; Female; Functional Laterality; Homovanillic Acid; Humans; Male; Motor Skills Disorders; Neuropsychological Tests; Positron-Emission Tomography; Putamen; Raclopride; Receptors, Dopamine D2; Sex Factors