Monoamine oxidase-A (MAO-A) is a treatment target in neurodegenerative illness and mood disorders that increases oxidative stress and predisposition toward apoptosis. Increased MAO-A levels in prefrontal cortex (PFC) and anterior cingulate cortex (ACC) occur in rodent models of depressive behavior and human studies of depressed moods. Extreme dysphoria is common in borderline personality disorder (BPD), especially when severe, and the molecular underpinnings of severe BPD are largely unknown. We hypothesized that MAO-A levels in PFC and ACC would be highest in severe BPD and would correlate with symptom magnitude.[11C] Harmine positron emission tomography measured MAO-A total distribution volume (MAO-A VT), an index of MAO-A density, in severe BPD subjects (n = 14), moderate BPD subjects (n = 14), subjects with a major depressive episode (MDE) only (n = 14), and healthy control subjects (n = 14). All subjects were female.Severe BPD was associated with greater PFC and ACC MAO-A VT compared with moderate BPD, MDE, and healthy control subjects (multivariate analysis of variance group effect: F6,102 = 5.6, p < .001). In BPD, PFC and ACC MAO-A VT were positively correlated with mood symptoms (PFC: r = .52, p = .005; ACC: r = .53, p = .004) and suicidality (PFC: r = .40, p = .037; ACC: r = .38, p = .046), while hippocampus MAO-A VT was negatively correlated with verbal memory (r = −.44, p = .023).These results suggest that elevated MAO-A VT is associated with multiple indicators of BPD severity, including BPD symptomatology, mood symptoms, suicidality, and neurocognitive impairment.

BACKGROUND:Previous reports suggest that some atypical antipsychotics may have obsessogenic as well as antiobsessional effects. Given their higher affinity for serotonin 5HT2 receptors than dopamine D2 receptors, it has been speculated that atypical antipsychotics may induce obsessive-compulsive (OC) symptoms, even at low doses, due to high 5HT2 antagonism, whereas improvement in OC symptoms is thought to occur only at high doses due to high D2 antagonism.METHOD:In this open case series, the dose-response relationship of atypical antipsychotic augmentation in the treatment of obsessive compulsive disorder (OCD), and the dose-severity relationship in atypical anti psychotic-induced OC symptoms were examined. Three patients were identified who had either refractory OCD or OC symptoms following administration of atypical antipsychotics such as olanzapine and risperidone.RESULTS:Case 1: A linear dose-response relationship between increasing doses of olanzapine and improvement in OC symptoms was observed in an OCD patient resistant to 5-HT reuptake inhibitors. 2: OC symptoms induced by low doses of risperidone (1 mg) were reversed by increasing the doses of risperidone (3 mg) in a bipolar disorder patient suggesting an inverse dose-severity relationship. 3: No inverse dose-severity relationship was noted between olanzapine induced OC symptoms and its dosage in an asymptomatic OCD patient. Tretment-emergence OC symptoms responded to increasing the doses of maintanance clomipramine treatment.CONCLUSIONS:Controlled studies are needed to investigate the dose-response or dose-severity relationships between OCD and atypical antipsychotics.

Background: Recent studies have suggested clinical differences among selective serotonin reuptake inhibitors. In a 12-week randomized, multicenter, double-blind trial, the antidepressant and anxiolytic efficacy of the selective serotonin reuptake inhibitors paroxetine and fluoxetine was compared in patients with moderate to severe depression.Methods: A total of 203 patients were randomized to fixed doses (20 mg/day) of paroxetine or fluoxetine for the first six weeks of therapy. From week 7-12, dosing could be adjusted biweekly, as required (paroxetine 20-50 mg/day, and fluoxetine 20-80 mg/day). The mean prescribed doses were paroxetine 25.5 mg/day (range 20.0-40.2 mg/day), and fluoxetine 27.5 mg/day (range 20.0-59.5 mg/day). Emergence of motor nervousness or restlessness was assessed using the ESRS scale for akathisia.Results: Both active treatments demonstrated comparable antidepressant efficacy (HAM-D, CGI). Anxiolytic activity of the two drugs (COVI, STAI, KAM-D) was also comparable. However, paroxetine was found to be superior to fluoxetine on two subscore measures at week 1 of therapy (HAM-D Agitation item, p < 0.05; Psychic Anxiety item, p <0.05), with no differences detected after week 2. The overall incidence of adverse effects was comparable in the two treatment groups. Constipation, dyspepsia, tremor, sweating and abnormal ejaculation were more common in paroxetine-treated subjects, whereas nausea and nervousness were more frequent in fluoxetine-treated patients. Weight loss was more common in the fluoxetine versus paroxetine group (11.88% versus 2.94%, respectively). ESRS scores for akathisia were low throughout the study and showed little change.Limitations: Differences observed between the two drugs in antianxiety effects were limited to two measures of anxiety among several others.Discussion: The data indicate that paroxetine and fluoxetine have comparable,antidepressant and anxiolytic efficacy. Paroxetine appears to produce an earlier improvement in agitation and psychic anxiety symptoms compared with fluoxetine. (C) 1999 Elsevier Science B.V. All rights reserved.

The effects of treatment with serotonin (5-HT) reuptake inhibitors on platelet 5-HT2 receptors, 5-HT reuptake sites and 5-HT uptake were studied in a double-blind trial comparing two selective serotonin reuptake inhibitors (SSRI), paroxetine, and fluoxetine, for the treatment of major depression, Hamilton Depression Rating Scale (HAM-D) scores and platelet 5-HT parameters were determined in 21 depressed patients at baseline, after 4 and 8 weeks of treatment, and were compared to 21 healthy controls, Antidepressant treatment did not significantly alter the density of 5-HT reuptake sites, labelled with [H-3]paroxetine, or 5-HT2 receptors, labelled with [H-3]LSD, However, a strong correlation was observed between the HAM-D suicidality item and 5-HT2 receptor density at baseline, A marked increase in platelet 5-HT2 receptors at baseline was observed in suicidal depressed patients compared to those with no suicidal ideation and healthy controls, Changes in [H-3]paroxetine Bmax and in [H-3] 5-HT uptake significantly correlated with change in HAM-D score at 4 and 8 weeks respectively, These results confirm previous reports of an association between suicidality and platelet 5-HT2 receptor upregulation, Our data also fends support to the use of platelet 5-HT parameters as indicators of antidepressant efficacy, particularly in suicidal depressed patients. (C) 1997 Society of Biological Psychiatry

The uptake of [H-3]5-HT and the density (B(max)) as well as affinity (Kd) of 5-HT uptake sites labelled with [H-3]paroxetine and of 5-HT2 receptors labelled by [H-3]LSD were determined in platelets from 25 medication-free patients with major depression and 20 normal controls. The density (B(max)) of 5-HT2 receptors was found to be significantly increased (by 52%) in platelets from depressed patients, particularly females. No changes were found in the affinity (Kd) of 5-HT2 receptors and in 5-HT uptake or [H-3]paroxetine binding parameters. Density of 5-HT2 receptors positively correlated with that of [H-3]paroxetine sites in control but not in depressed subjects. No correlation was found between the HAMD scores and B(max) of [H-3]LSD binding. The results suggest that upregulation of platelet 5-HT2 receptors is a useful biological marker in major depression, particularly in females.

Paroxetine is an effective antidepressant drug and potent serotonin (5-HT) uptake inhibitor. It selectively labels 5-HT transporter on platelets and neurons. We report here the synthesis of an aryl-azido derivative of paroxetine, which is a novel photoactive and irreversible ligand for the [3H]paroxetine binding site on the platelet 5-HT transporter. The compound inhibited [3H]paroxetine binding (ic50, 55 nM) and 5-HT uptake (ic50, 12 nM) at equilibrium conditions and inactivated 10–20% of [3H]paroxetine binding sites upon irradiation at 320 nm. SDS-PAGE of platelet protein extract labelled with the radioactive analogue of the synthesized probe revealed the presence of four radioactive bands of which the 71-kDa one was the most prominent

The reversible inhibitors of monoamine oxidase type A (RIMAs) are a newer group of antidepressants that have had much less impact on clinical psychopharmacology than another contemporary class of medications, the selective serotonin reuptake-inhibitors (SSRIs). The RIMAs agents are distinguished from the older monoamine oxidase inhibitors (MAOIs) by their selectivity and reversibility. As a result, dietary restrictions are not required during RIMA therapy, and hypertensive crises are quite rare. In this article, we describe a series of meta-analyses of studies of the two most widely researched RIMAs, moclobemide (MOC; Aurorex) and brofaromine (BRO). Our findings confirm that both BRO and MOC are as effective as the tricyclic antidepressants, and they are better tolerated. However, BRO is not being studied at present for reasons unrelated to efficacy or side effects. MOC, which is available throughout much of the world (but not the United States), is significantly more effective than placebo and, at the least, comparable to the SSRIs in both efficacy and tolerability. For MOC, higher dosages may enhance efficacy for more severe depressions. We also found evidence that supports clinical impressions that MOC is somewhat less effective, albeit better tolerated, than older MAOIs, such as phenelzine or tranylcypromine. Little evidence has yet emerged to suggest that the RIMAs share older MAOIs’ utility for treatment of depressions characterized by prominent reverse neurovegetative features. Based on available evidence, the RIMAs appear to have a limited, but useful, role in the differential therapeutics of the depressive disorders.

Institute of Mental Health Research, Royal Ottawa Hospital, 1145 Carling Avenue, Otfowa, Ontario, Canada K1Z 7K4

Two hundred and forty-two patients with acute schizophrenia were enrolled in a double-blind, comparative, dose-finding study of a novel antipsychotic, remoxipride. Remoxipride was evaluated in a low (30 to 90 mg), medium (120 to 240 mg) and a high (300 to 600 mg) dose range and compared with a haloperidol (15 to 45 mg), which was administered to a similar group of patients. The results support the antipsychotic effect of remoxipride, with maximum efficacy occurring at daily doses between 120 mg and 600 mg. Side-effects were more frequent at doses of remoxipride over 300 mg. In all groups, remoxipride caused consistently fewer extrapyramidal side-effects than haloperidol. The antipsychotic effect of remoxipride may be derived from specific blockade of dopamine D2 receptors in the mesolimbic tract. The findings also suggest that remoxipride may have a therapeutic effect on negative symptoms of schizophrenia.