Augmentation Of Serotonin Reuptake Inhibitors Research Articles

Positron emission tomography study of pindolol occupancy of 5-HT 1A receptors in humans: preliminary analyses

Preclinical studies in rodents suggest that augmentation of serotonin reuptake inhibitors (SSRIs) therapy by the 5-hydroxytryptamine 1A (5-HT 1A) receptor agent pindolol might reduce the delay between initiation of treatment and antidepressant response. This hypothesis is based on the ability of pindolol to potentiate the increase in serotonin (5-HT) transmission induced by SSRIs, an effect achieved by blockade of the 5-HT 1A autoreceptors in the dorsal raphe nuclei (DRN). However, placebo-controlled clinical studies of pindolol augmentation of antidepressant therapy have reported inconsistent results. Here, we evaluated the occupancy of 5-HT 1A receptors following treatment with controlled release pindolol in nine healthy volunteers with positron-emission tomography (PET). Each subject was studied four times: at baseline (scan 1), following 1 week of oral administration of pindolol CR (7.5 mg/day) at peak level, 4 h after the dose (scan 2), and at 10 h following the dose (scan 3), and following one dose of pindolol CR (30 mg) (at peak level, 4 h) (scan 4). Pindolol occupancy of 5-HT 1A receptors was evaluated in the DRN and cortical regions as the decrease in binding potential (BP) of the radiolabelled selective 5-HT 1A antagonist [ carbonyl- 11C]WAY-100635 or [ carbonyl- 11C] N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)- N-(2-pyridyl)cyclohexanecarboxamide abbreviated as [ 11C]WAY-100635. Pindolol dose-dependently decreased [ 11C]WAY-100635 BP. Combining all the regions, occupancy was 20 ± 8% at scan 2, 14 ± 8% at scan 3, and 44 ± 8% at scan 4. The results of this study suggest that at doses used in clinical studies of augmentation of the SSRI effect by pindolol (2.5 mg t.i.d.), the occupancy of 5-HT 1A receptors is moderate and highly variable between subjects. This factor might explain the variable results obtained in clinical studies. On the other hand, at each dose tested, pindolol occupancy of 5-HT 1A receptors was higher in the DRN compared to cortical regions, demonstrating a significant in vivo selectivity for DRN 5-HT 1A autoreceptors relative to cortico-limbic postsynaptic receptors. This selectivity is necessary for the potentiation of 5-HT transmission, and this finding represents an important proof of concept in the development of 5-HT 1A agents for this application. Early evaluation of new drugs with PET imaging will enable rapid screening of compounds based on DRN selectivity and more appropriate determination of doses for clinical trials.

Lamotrigine augmentation of serotonin re-uptake inhibitors in obsessive-compulsive disorder

Lamotrigine augmentation of serotonin re-uptake inhibitors in obsessive-compulsive disorder

Augmentation with a 5-HT 1A, but not a 5-HT 1B receptor antagonist critically depends on the dose of citalopram

Pharmacokinetic and pharmacodynamic parameters of the selective serotonin reuptake inhibitor 1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-5-phtalancarbonitril (citalopram) were determined in order to find optimal conditions for augmentation of its effect on extracellular serotonin [5-hydroxytryptamine (5-HT)] through blockade of 5-HT 1A and 5-HT 1B autoreceptors. Citalopram dose-dependently (0.3–10 μmol/kg s.c.) increased serotonin levels in ventral hippocampus of conscious rats. At plasma levels above approximately 0.15 μM, the effect of citalopram on extracellular 5-HT was augmented by both a 5-HT 1A [ N-[2-[4-(2-mehoxyphenyl)-1-piperazinyl]ethyl]- N-(2-pyridil)cyclohexanecarboxamide trihydrochloride (Way 100635), 1 μmol/kg s.c.] and a 5-HT 1B receptor antagonist (2′-methyl-4′-(5-methyl-[1,2,4]oxadiazol-3-yl)biphenyl-4-carboxylic acid [4-methoxy]-3-(4-methylpiperazin-1-yl)phenyl]amide (GR 127935), 1 μmol/kg s.c.). However, at plasma levels of the selective serotonin reuptake inhibitor below 0.15 μM, the effects of the antagonists diverged viz. the 5-HT 1B receptor antagonist was still able to potentiate citalopram's effect on extracellular 5-HT, while the 5-HT 1A receptor antagonist was no longer effective. These results suggest that in contrast to 5-HT 1B autoreceptors, indirect activation of 5-HT 1A autoreceptors by citalopram is critically related to the dose of selective serotonin reuptake inhibitor administered. The latter may have consequences for selective serotonin reuptake inhibitor augmentation strategies with 5-HT 1A receptor antagonists in the therapy of depression and anxiety disorders.

Inositol versus placebo augmentation of serotonin reuptake inhibitors in the treatment of obsessive-compulsive disorder: a double-blind cross-over study.

Current serotonin reuptake inhibitor (SRI) treatments for obsessive-compulsive disorder (OCD) provide only partial benefit. A previous study suggested that inositol alone is efficacious in OCD. Ten DSM-IV OCD patients completed a study of 18 g inositol or placebo for 6 wk each in addition to ongoing SRI treatment in a double-blind randomized cross-over design. Weekly assessments included the Yale-Brown Obsessive-Compulsive Scale (YBOCS) and Hamilton Depression and Anxiety scales. No significant difference was found between the two treatment phases.

Risperidone augmentation of serotonin reuptake inhibitors in obsessive-compulsive and related disorders.

While serotonin is the neurotransmitter most commonly implicated in obsessive-compulsive and related disorders, there is also evidence for dopaminergic mediation of these conditions. Indeed, augmentation of serotonin reuptake inhibitors with the atypical neuroleptic risperidone has been suggested to be useful in obsessive-compulsive disorder (OCD). Charts of all patients treated in our OCD clinic with the combination of a serotonin reuptake inhibitor and risperidone were reviewed. Demographic details of patients and clinical response to this pharmacotherapeutic strategy were tabulated. A series of patients with OCD (N = 8), trichotillomania (N = 5), and Tourette's syndrome (N = 3) who were refractory to treatment with serotonin reuptake inhibitors had received risperidone augmentation. In a number of cases, this strategy proved clinically effective. However, a minority of patients experienced significant adverse effects. Patients with OCD and related disorders are not infrequently refractory to treatment with serotonin reuptake inhibitors. Controlled trials of risperidone augmentation in such patients seem warranted. In particular, it is necessary to determine an appropriate dose range to minimize adverse effects.