PET imaging shows no changes in TSPO brain density after IFN-α immune challenge in healthy human volunteers.

Depression is associated with peripheral inflammation, but its link with brain microglial activity remains unclear. In seven healthy males, we used repeated translocator protein-Positron Emission Tomography (TSPO-PET) dynamic scans with [11C]PBR28 to image brain microglial activation before and 24 h after the immune challenge interferon (IFN)-α. We also investigated the association between changes in peripheral inflammation, changes in microglial activity, and changes in mood. IFN-α administration decreased [11C]PBR28 PET tissue volume of distribution (Vt) across the brain (-20 ± 4%; t6 = 4.1, p = 0.01), but after correction for radioligand free-plasma fraction there were no longer any changes (+23 ± 31%; t = 0.1, p = 0.91). IFN-α increased serum IL-6 (1826 ± 513%, t6 = -7.5, p < 0.001), IL-7 (39 ± 12%, t6 = -3.6, p = 0.01), IL-10 (328 ± 48%, t6 = -12.8, p < 0.001), and IFN-γ (272 ± 64%, t6 = -7.0, p < 0.001) at 4-6 h, and increased serum TNF-α (49 ± 7.6%, t6 = -7.5, p < 0.001), IL-8 (39 ± 12%, t6 = -3.5, p = 0.013), and C-reactive protein (1320 ± 459%, t6 = -7.2, p < 0.001) at 24 h. IFN-α induced temporary mood changes and sickness symptoms after 4-6 h, measured as an increase in POMS-2 total mood score, confusion and fatigue, and a decrease in vigor and friendliness (all p ≤ 0.04). No association was found between changes in peripheral inflammation and changes in PET or mood measures. Our work suggests that brain TSPO-PET signal is highly dependent of inflammation-induced changes in ligand binding to plasma proteins. This limits its usefulness as a sensitive marker of neuroinflammation and consequently, data interpretation. Thus, our results can be interpreted as showing either that [11C]PBR28 is not sensitive enough under these conditions, or that there is simply no microglial activation in this model.

Low-dose clozapine in acute and continuation treatment of severe borderline personality disorder.

BACKGROUND: Psychotic-like symptoms in patients affected by borderline personality disorder (BPD) are usually treated with low-dose neuroleptics, which show controversial acute effects and lead to a worsening of affective-related symptoms and to severe neurologic side effects after prolonged administration. Clozapine lacks the neurologic side effects of traditional neuroleptics and has been shown to successfully treat psychotic-like symptoms in BPD patients at medium dose. We performed an open-label trial of low-dose clozapine in severe BPD patients. METHOD: Twelve BPD inpatients (DSM-IV criteria) with severe psychotic-like symptoms were studied. Exclusion criteria included comorbid Axis I and medical pathologies. All patients had followed a therapeutic program without improvement for at least 4 months before admission. The clozapine dose was titrated upward on an individual basis until the complete disappearance of psychotic-like symptoms was achieved. Clinician-rated scales were completed at the beginning of the study and after 4 and 16 weeks. RESULTS: All patients completed the 16-week study. Individual clozapine doses ranged from 25 to 100 mg/day. Psychotic-like symptoms decreased within the first 3 weeks of treatment, as confirmed by a statistically significant decrease in Brief Psychiatric Rating Scale scores. This amelioration was coupled with an overall improvement, including a reduction in impulsive behaviors and in affective-related symptoms (Hamilton Rating Scale for Depression) and an increase in global functioning (Global Assessment of Functioning). CONCLUSION: Low-dose clozapine for acute and continuation treatment led to improvement in overall symptomatology in a small sample of severe BPD patients.

How long should pindolol be associated with paroxetine to improve the antidepressant response?

A double-blind study was undertaken to investigate the period of treatment with the beta-adrenoreceptor/5-hydroxytryptamine 1A (5-HT1A) antagonist pindolol required to enhance the antidepressant effects of paroxetine. After 1 week of a placebo run-in period, 63 untreated major depressive inpatients were randomly assigned to three different groups. Group 1 received paroxetine (20 mg/day) plus placebo (4 weeks). Group 2 received paroxetine (20 mg/day) plus pindolol (7.5 mg/day) for 1 week and placebo for 3 weeks. Group 3 received both active treatments for the entire duration of the study (4 weeks). Clinical response was defined as a reduction of the score in the Hamilton Rating Scale for Depression (HAM-D) to 8 or below. Also, to preliminarily examine whether beta-adrenoreceptor blockade was involved in the action of pindolol, another group of 10 inpatients was treated in an open-label manner with paroxetine (20 mg/day) plus 50 mg/day of the beta-adrenergic antagonist metoprolol, devoid of significant affinity for 5-HT1A receptors. At endpoint, the incidence of treatment-emergent side effects did not significantly differ among the three groups. After 1 and 2 weeks of treatment, the two groups treated with paroxetine plus pindolol displayed a significantly greater response rate than the group treated with paroxetine plus placebo. At study completion, only the patients treated with pindolol for the entire period showed a significantly greater response rate (p = 0.05). HAM-D score were also significantly lower at endpoint in patients treated with the combination for 4 weeks (p = 0.00003). The group of patients treated with paroxetine and metoprolol exhibited a side-effect profile comparable to that of paroxetine alone. Response rates were also comparable. These findings support the efficacy of pindolol, but not of metoprolol, in accelerating the antidepressant effect of paroxetine and suggest that the administration of pindolol for the entire period of the acute treatment may increase the efficacy of paroxetine.