Brain neurokinin-1 receptor availability in never-medicated patients with major depression - A pilot study.

BACKGROUND: Neurotransmitter substance P (SP) and its preferred neurokinin-1 receptor (NK1R) have been implicated in the treatment of affective and addiction disorders. Despite promising preclinical data on antidepressant action, the clinical trials of NK1R antagonists in major depression have been disappointing. There are no direct in vivo imaging studies on NK1R characteristics in patients with a major depressive disorder (MDD). METHODS: In this cross-sectional case-control study, we recruited nine never-medicated patients with moderate to severe MDD and nine matched healthy controls. NK1R availability (NK1R binding potential, BPND) was measured with in vivo 3-D positron emission tomography and a specific NK1 receptor tracer [18F]SPA-RQ. Clinical symptoms were assessed with the 17-item Hamilton Rating Scale for Depression (HAM-D17). RESULTS: NK1R-BPND did not differ statistically significantly between patients with MDD and healthy controls. HAM-D17 total scores (range 21-32) correlated positively with NK1R-BPND in cortical and limbic areas. HAM-D17 subscale score for anxiety symptoms correlated positively with NK1R-BPND in specific brain areas implicated in fear and anxiety. LIMITATIONS: Small sample size. Low variability in the clinical HAM-D subscale ratings may affect the observed correlations. CONCLUSIONS: Our preliminary results do not support a different baseline expression of NK1Rs in a representative sample of never-medicated patients with MDD during a current moderate/severe depressive episode. The modulatory effect of NK1Rs on affective symptoms is in line with early positive results on antidepressant action of NK1 antagonists. However, the effect is likely to be too weak for treatment of MDD with NK1R antagonists alone in clinical practice.

Effects of antidepressant drug treatment and psychotherapy on striatal and thalamic dopamine D2/3 receptors in major depressive disorder studied with [11C]raclopride PET.

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.

Personality traits and recovery from major depressive disorder.

OBJECTIVE: To study the correlation of personality traits measured by the Temperament and Character Inventory (TCI) with the prognosis of major depressive disorder in patients treated with either fluoxetine or short-term psychodynamic psychotherapy in a randomized comparative study. METHOD: 35 patients with DSM IV-defined major depressive disorder of mild or moderate severity were randomized to receive either short-term psychodynamic psychotherapy or fluoxetine treatment for 16 weeks. Prior to beginning of the therapy, patients were assessed with TCI. The Hamilton Depression Rating Scale (HDRS) was used as the outcome measure completed at the baseline and follow-up at 4 months. RESULTS: In the combined group (n=35), Harm Avoidance was associated with the severity of the depression measured by the HDRS at the baseline (P=0.01) and baseline Self-Directedness with the HDRS at 4 months follow-up (P=0.03). In the fluoxetine treatment group, Reward Dependence (P=0.03), Self-Directedness (P=0.01) and Cooperativeness (P=0.02) at the baseline associated with HDRS at 4 months follow-up. No statistically significant associations between personality traits and depression scores at the follow-up were found in the patients treated with psychotherapy. CONCLUSION: In this whole cohort of depressive patients, baseline high Self-Directedness predicted higher depression scores after 4 months of treatment. In the fluoxetine treatment group, subjects with high baseline Reward Dependence, Self-Directedness or Cooperativeness were likely more severely depressed at the 4 months follow-up. We suggest that associations between personality traits and remaining depressive symptoms after 4 months treatment with fluoxetine could be caused by the potential differences in the placebo effect.

The effects of lorazepam on extrastriatal dopamine D(2/3)-receptors-A double-blind randomized placebo-controlled PET study.

Lorazepam is a widely used anxiolytic drug of the benzodiazepine class. The clinical actions of benzodiazepines are thought to be mediated via specific allosteric benzodiazepine binding sites and enhancement of GABAergic neurotransmission in the brain. However, the indirect effects of benzodiazepines on other neurotransmitter systems have not been extensively studied. Previous experimental evidence suggests that benzodiazepines inhibit striatal dopamine release by enhancing the GABAergic inhibitory effect on dopamine neurons whereas very little is known about cortical or thalamic gamma-amino-butyric (GABA)-dopamine interactions during benzodiazepine administration. We explored the effects of lorazepam (a single 2.5 mg dose) on cortical and thalamic D(2/3) receptor binding using Positron-Emission Tomography (PET) and the high-affinity D(2/3)-receptor ligand [(11)C]FLB 457 in 12 healthy male volunteers. We used a randomized, double-blind and placebo-controlled study design. Dopamine D(2)/D(3) receptor binding potential was measured with the reference tissue method in several extrastriatal D(2)-receptor areas including frontal, parietal, temporal cortices and thalamus. The main subjective effect of lorazepam was sedation. Lorazepam induced a statistically significant decrease of D(2)/D(3) receptor BP(ND) in medial temporal and dorsolateral prefrontal cortex (DLPFC) that was also confirmed by a voxel-level analysis. The sedative effect of lorazepam was associated with a decrease in D(2)/D(3) receptor BP(ND) in the DLPFC. In conclusion, lorazepam decreased [(11)C]FLB 457 binding in frontal and temporal cortex, suggesting that cortical GABA-dopamine interaction may be involved in the central actions of lorazepam in healthy volunteers. The correlation between lorazepam-induced sedation and D(2)/D(3) receptor binding potential (BP) change further supports this hypothesis.

Does defense style or psychological mindedness predict treatement response in major depression?

BACKGROUND: The aim of this study was to define the impact of defense style and psychological mindedness (PM) on the prognosis of major depressive disorder (MDD) in patients treated with either fluoxetine (FLX) or short-term psychodynamic psychotherapy (STPP) in a randomized comparative study. METHOD: 50 patients with MDD received either STPP or FLX treatment for 16 weeks. The Hamilton Depression Rating Scale (HDRS) was the outcome measure completed at baseline and in the follow-ups at 4- and 12-months. Patients completed the Psychological Mindedness Scale (PMS) and the Defense Style Questionnaire at the baseline. RESULTS: In the FLX group recovery measured by the decrease in the HDRS during the 4-month follow-up associated with baseline mature defense style (r=-.59, P=.015). There were no correlations between the PMS-scores and the outcome measures in either treatment groups nor defense status and the outcome in the STPP group. CONCLUSION: Mature defense style predicts good response to FLX therapy in major depression. This association was not found in the psychotherapy group. The results may imply that patients with immature defenses benefit relatively more from brief psychotherapy than medication. PM measured by the PMS was not useful in predicting recovery in MDD.

Differential associations between brain 5-HT(1A) receptor binding and response to pain versus touch.

We studied whether brain serotonin 5-HT(1A) receptor availability is associated with response to noxious heat versus tactile stimuli, and short-term memory for heat pain. Psychophysical performance was assessed in 16 healthy subjects who had participated in a positron emission tomography study using [carbonyl-11C]WAY-100635 ligand for the assessment of 5-HT(1A) receptor binding potential (BP (ND)). Signal detection theory was applied to allow separate analysis of the subject's sensory-discriminative capacity (sensory factor) and the attitude toward reporting a sensation (response criterion; non-sensory factor). Subject's response criterion for heat pain was inversely correlated with 5-HT(1A) BP (ND) in the dorsal raphe, middle temporal gyrus, orbitofrontal cortex and posterior cingulum, whereas the subject's discriminative capacity for touch was inversely correlated with 5-HT(1A) BP (ND) in the cingulum, inferior temporal gyrus, and medial prefrontal cortex. Certainty ratings of the responses, but not hit rates, in the pain memory task were correlated with 5-HT(1A) BP (ND) in the dorsal raphe.

The effects of d-amphetamine on extrastriatal dopamine D2/D3 receptors: a randomized, double-blind, placebo-controlled PET study with [11C]FLB 457 in healthy subjects.

PURPOSE: The dopamine D(2)/D(3) receptor ligand [(11)C]FLB 457 and PET enable quantification of low-density extrastriatal D(2)/D(3) receptors, but it is uncertain whether [(11)C]FLB 457 can be used for measuring extrastriatal dopamine release. METHODS: We studied the effects of d-amphetamine (0.3 mg/kg i.v.) on extrastriatal [(11)C]FLB 457 binding potential (BP(ND)) in a randomized, double-blind, placebo-controlled study including 24 healthy volunteers. RESULTS: The effects of d-amphetamine on [(11)C]FLB 457 BP(ND) and distribution volume (V(T)) in the frontal cortex were not different from those of placebo. Small decreases in [(11)C]FLB 457 BP(ND) were observed only in the posterior cingulate and hippocampus. The regional changes in [(11)C]FLB 457 BP(ND) did not correlate with d-amphetamine-induced changes in subjective ratings of euphoria. CONCLUSION: This placebo-controlled study showed that d-amphetamine does not induce marked changes in measures of extrastriatal dopamine D(2)/D(3) receptor binding. Our results indicate that [(11)C]FLB 457 PET is not a useful method for measuring extrastriatal dopamine release in humans.

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

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

RATIONALE: 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. OBJECTIVE: To study the striatal and thalamic dopamine D2 receptor availability in drug-naive patients with major depression was the aim of this study. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

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.