Modification of the association between paroxetine serum concentration and SERT-occupancy by ABCB1 (P-glycoprotein) polymorphisms in major depressive disorder

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) exert substantial variability in effectiveness in patients with major depressive disorder (MDD), with up to 50-60% not achieving adequate response. Elucidating pharmacokinetic factors that explain this variability is important to increase treatment effectiveness. OBJECTIVES: To examine potential modification of the relationship between paroxetine serum concentration (PSC) and serotonin transporter (SERT)-occupancy by single nucleotide polymorphisms (SNPs) of the ABCB1 gene, coding for the P-glycoprotein (P-gp) pump, in MDD patients. To investigate the relationship between ABCB1 SNPs and clinical response. METHODS: Patients had MDD and received paroxetine 20 mg/day. We measured PSC after 6 weeks. We quantified SERT-occupancy with SPECT imaging (n = 38) and measured 17-item Hamilton Depression Rating Scale (HDRS17)-scores at baseline and after 6 wee

Evidence Why Paroxetine Dose Escalation is Not Effective in Major Depressive Disorder: A Randomized Controlled Trial With Assessment of Serotonin Transporter Occupancy

Dose escalation is often used in depressed patients who fail to respond to standard doses of selective serotonin reuptake inhibitors, but clinical efficacy is equivocal. We aimed to reassess the efficacy of paroxetine dose escalation and quantify whether paroxetine dose escalation increases occupancy of the serotonin transporter (SERT) more than placebo dose escalation in a randomized controlled trial. We recruited 107 nonpsychotic, unipolar depressed outpatients (18-70 years; Hamilton Depression Rating Scale (HDRS(17)) >18) from primary care and psychiatric outpatient departments. After 6 weeks, open-label paroxetine 20 mg per day (T0), nonresponding patients (HDRS(17) decrease 0.5)). Overall dropout was higher for placebo (26.7%) than paroxetine (3.3%; p=0.03). Paroxetine dose escalation increased paroxetine serum concentrations (p <0.001). SPECT measurements (12 patients randomized to paroxetine (46.9+/-4.8 mg) and 14 to placebo dose escalation) showed no significant increase of midbrain SERT occupancy (2.5+/-26.4%, paroxetine; 3.1+/-25.8% placebo; p=0.687) nor in diencephalon (p=0.529). Paroxetine dose escalation in depressed patients has no clinical benefit over placebo dose escalation. This is explained by the absence of significant increases of SERT occupancy by paroxetine dose escalation, despite increased paroxetine serum concentrations (ISRCTN44111488).Neuropsychopharmacology advance online publication, 1 October 2008; doi:10.1038/npp.2008.14

Transversal images of D2/3R availability.

<p>Transversal [123I]IBZM SPECT slices at the level of the striatum showing D2/3 receptor availability in a TRD patient, a TRD patient on antipsychotics (TRD AP), and a healthy control subject.</p

Striatal D2/3R availability for TRD, TRD AP and healthy control subjects.

<p>Striatal D2/3 receptor (D2/3R) availability of TRD patients, TRD patients with antipsychotics (TRD AP) and healthy control subjects. The black dots represents the striatal D2/3R availability of each subject. The horizontal lines indicate the mean D2/3R availability of each group which is 0.84 for the TRD, 0.50 for the TRD AP and 0.81 for the healthy control subjects.</p

Psychopharmacological drugs used in TRD and TRD AP patients.

<p>Psychopharmacological drugs used in TRD and TRD AP patients.</p

Striatal Dopamine D-2/3 Receptor Availability in Treatment Resistant Depression

Several studies demonstrated improvement of depressive symptoms in treatment resistant depression (TRD) after administering dopamine agonists which suggest abnormal dopaminergic neurotransmission in TRD. However, the role of dopaminergic signaling through measurement of striatal dopamine D-2/3 receptor (D2/3R) binding has not been investigated in TRD subjects. We used [I-123] IBZM single photon emission computed tomography (SPECT) to investigate striatal D2/3R binding in TRD. We included 6 severe TRD patients, 11 severe TRD patients on antipsychotics (TRD AP group) and 15 matched healthy controls. Results showed no significant difference (p = 0.75) in striatal D2/3R availability was found between TRD patients and healthy controls. In the TRD AP group D2/3R availability was significantly decreased (reflecting occupancy of D2/3Rs by antipsychotics) relative to TRD patients and healthy controls (p <0.001) but there were no differences in clinical symptoms between TRD AP and TRD patients. This preliminary study therefore does not provide evidence for large differences in D2/3 availability in severe TRD patients and suggests this TRD subgroup is not characterized by altered dopaminergic transmission. Atypical antipsychotics appear to have no clinical benefit in severe TRD patients who remain depressed, despite their strong occupancy of D2/3Rs