Antidepressant medication exposure and 5-HT1A autoreceptor binding in major depressive disorder.

OBJECTIVE: We have previously reported higher brain serotonin 1A (5-HT1A ) autoreceptor binding in antidepressant-naïve patients with Major Depressive Disorder (MDD) compared with healthy volunteers, and a decrease in binding in MDD after selective serotonin reuptake inhibitor (SSRI) treatment. This SSRI effect is also present in rodents administered SSRIs chronically. We therefore sought to determine the duration of antidepressant medication effects on 5-HT1A receptor binding after medication discontinuation. METHODS: Positron emission tomography (PET) imaging with the 5-HT1A receptor radioligand [11 C]WAY-100635 was performed in 66 individuals with current DSM-IV MDD to examine relationships between 5-HT1A binding and time since most recent antidepressant treatment. All subjects were medication-free for at least 2 weeks prior to scanning. Thirty-two additional MDD comparison subjects were antidepressant naïve. RESULTS: No differences in [11 C]WAY-100635 binding were observed between antidepressant naïve and antidepressant exposed MDD groups in 13 a priori cortical and subcortical regions of interest, including raphe autoreceptors, assessed simultaneously in linear mixed effects models. Furthermore, [11 C]WAY-100635 binding did not correlate with time off antidepressants in the antidepressant exposed patients considering these ROIs. The same results were observed when effects of treatment discontinuation of any psychotropic medication used to treat their depression was examined. CONCLUSION: These results indicate that any antidepressant-associated downregulation of 5-HT1A autoreceptor binding reverses within 2 weeks of medication discontinuation. Since this effect is hypothesized to mediate the antidepressant action of SSRIs, and perhaps other antidepressants, it suggests that patients who need ongoing treatment may relapse rapidly when medication is discontinued. Moreover, 2 weeks appears to be a sufficiently long washout of antidepressant medications for a reliable measure of illness-related binding levels.

A pilot in vivo proton magnetic resonance spectroscopy study of amino acid neurotransmitter response to ketamine treatment of major depressive disorder.

The N-methyl-D-aspartate receptor antagonist ketamine can improve major depressive disorder (MDD) within hours. To evaluate the putative role of glutamatergic and GABAergic systems in ketamine's antidepressant action, medial prefrontal cortical (mPFC) levels of glutamate+glutamine (Glx) and γ-aminobutyric acid (GABA) were measured before, during, and after ketamine administration using proton magnetic resonance spectroscopy. Ketamine (0.5 mg kg(-1) intravenously) was administered to 11 depressed patients with MDD. Glx and GABA mPFC responses were measured as ratios relative to unsuppressed voxel tissue water (W) successfully in 8/11 patients. Ten of 11 patients remitted (50% reduction in 24-item Hamilton Depression Rating Scale and total score ⩽10) within 230 min of commencing ketamine. mPFC Glx/W and GABA/W peaked at 37.8%±7.5% and 38.0%±9.1% above baseline in ~26 min. Mean areas under the curve for Glx/W (P=0.025) and GABA/W (P=0.005) increased and correlated (r=0.796; P=0.018). Clinical improvement correlated with 90-min norketamine concentration (df=6, r=-0.78, P=0.023), but no other measures.

Long-acting follicle-stimulating hormone analogs containing N-linked glycosylation exhibited increased bioactivity compared with o-linked analogs in female rats.

The effects of altering the number and type of additional carbohydrate moieties on the pharmacokinetic and pharmacodynamic properties of FSH were examined in this report. A series of single-chain follitropins, containing variable numbers of additional N- (or O-) linked carbohydrates, were designed and expressed in Chinese hamster ovary cells. Proper folding, efficient receptor binding, and signal transduction were confirmed by in vitro assays. Pharmacokinetic and pharmacodynamic parameters were evaluated in immature female Sprague Dawley rats. Increasing the number of glycosylation sites with either N- (or O-) linked moieties extended the elimination half-life as much as 2-fold compared with recombinant human FSH (rhFSH). However, there was a maximum elimination half-life such that further glycosylation provided no additional lengthening of the half-life. Conversely, biopotency, as assessed by inhibin A levels 74 h post injection, and follicle production were significantly higher for the N-linked analogs. Rats stimulated with the longest acting analogs (either N- or O-linked) showed significantly higher ovarian weights than rats receiving a single injection of rhFSH. The analog containing four additional N-linked sites (rhFSH-N4) had the greatest number of large, preovulatory follicles. Although the half-life of rhFSH-N4 displayed no further enhancement beyond the other longest acting analogs, this analog exhibited significantly increased biopotency in rats. This work provides the basis for the generation of a series of reagents potentially useful for therapeutic applications.

Development and characterization of a long-acting recombinant hFSH agonist.

BACKGROUND: Fusion of the carboxyterminal peptide (CTP) of hCG to FSH results in a follitropin agonist with an extended half-life, presumably due to the four O-oligosaccharides on the CTP. Alternatively, an rhFSH analogue containing additional N-linked carbohydrate is described in this report. METHODS: A DNA sequence containing two N-oligosaccharide signal sequences was ligated into a vector containing hFSHbeta- and alpha-subunit encoding cDNA, and expressed in CHO-K1 cells. In-vitro bioactivity of the single-chain hormone was assessed in CHO cells expressing the hFSH receptor. Pharmacokinetic values were derived from serial serum assays of the analogue in immature female rats following a single i.v. injection. In-vivo bioactivity was assessed by measuring ovarian weight gain 3 days post-injection. RESULTS: rhFSH-N2 and native rhFSH induced comparable levels of cAMP in vitro. t(1/2) for native rhFSH, rhFSH-CTP and rhFSH-N2 were 3.7, 7.1 and 7.3 h respectively. Rats receiving rhFSH-N2 had a mean +/- SD ovarian weight 3 days post-i.v. injection (22 +/- 3.6 mg) significantly greater than rats receiving rhFSH and saline (16.7 +/- 1.5 and 15.3 +/- 0.47 mg respectively, P < 0.05). CONCLUSIONS: rhFSH-N2 has prolonged half-life and increased bioactivity compared with native rhFSH. This rhFSH agonist, and other analogues containing additional N-oligosaccharides may have important clinical applications.

Variance decomposition of tempo drift in isochronous rhythmic tapping.

The statistical techniques developed herein show strong promise as a nonparametric extension of the classical Wing-Kristofferson decomposition of variance in isochronous tapping to include tempo drift. It is now important to establish the relative role of the three sources of variance in discriminating among unselected individuals as well as selected populations differentiated by such factors as age, gender, and motor control impairment. We are currently making the estimation techniques available through the web, so that they can be applied to extant and new data. We can be contacted by e-mail for further information.