Bipolar I and II disorder residual symptoms: oxcarbazepine and carbamazepine as add-on treatment to lithium in a double-blind, randomized trial.

Bipolar affective disorders often require adjunctive therapy to treat persistent symptoms. In order to evaluate bipolar symptoms inadequately responsive to lithium, we have compared the effects of two structurally related compounds carbamazepine (CBZ) and oxcarbazepine (OXC). We evaluated the efficacy and safety of CBZ and OXC administration in residual symptoms as an adjunctive therapy in Bipolar I (BP I) and Bipolar II (BP II) patients while on lithium maintenance treatment. We selected from 153 bipolar patients in treatment those fulfilling Research Diagnostic Criteria for mania or hypomania, according to the SADS-L and conducted in 52 bipolar patients (27 BP I, 25 BP II) a double-blind, randomized, parallel-group, single centre, clinical trial. Bipolar I and II outpatients, were randomly assigned on a 1:1 ratio to OXC (n=26) or CBZ (n=26) for an 8-week period as add-on treatment to the existing lithium regimen. Outcome measures included the Young Mania Rating Scale (YMRS), Hamilton Depression Rating Scale 21 items (HDRS-21) and Montgomery-Asberg Depression Rating Scale (MADRS), Clinical Global Impression severity (CGI-S) and improvement illness (CGI-I). These scales were administered at baseline and at the end of weeks 2, 4 and 8. All the fifty-two patients completed the trial. Overall, females were 35 (65%) and mean (S.D.) age was 39.4 (11.9) years; final doses at the end of week 8 in OXC group was 637.7 (210) mg/day and in the CBZ group 673.5 (179) mg/day; lithium plasma levels were 0.73 (0.25) meq/l and 0.71 (0.28) meq/l, respectively. Both OXC and CBZ were effective in reducing bipolar scores from baseline to endpoint (p<0.01). OXC was more effective than CBZ at weeks 4 and 8 on all 5 outcome measures. OXC resulted in greater significant mean reductions in YMRS, HDRS-21, MADRS, CGI-S and CGI-I scores from baseline to week 4 (p<0.05) and from baseline to week 8 (p<0.001), except YMRS (p<0.01). OXC appeared to be significantly more effective and with better tolerability than CBZ as add-on strategy treatment in BP I and BP II patients. This pilot, randomized clinical trial, suggests the potential usefulness of OXC as adjunctive therapy to lithium both in acute and long-term treatment of bipolar disorder. However, further adequately placebo-controlled trials are needed to expand these findings.

Influence of handling or aversive stimulation during rats' neonatal or adolescence periods on oral cocaine self-administration and cocaine withdrawal.

Adverse early life events may influence vulnerability for drug intake. The influence of handling or aversive stimulation during neonatal or adolescent periods on adult cocaine oral self-administration and withdrawal were investigated. Neonatal or adolescent rats were exposed to a modified unpredictable stress paradigm or handling for 10 days. When adults, oral cocaine was offered through the two-bottle choice paradigm for 30 days. Rats were submitted to the forced swimming test after cocaine withdrawal. Overall, there was a significant increase of cocaine choice throughout the days of cocaine consumption and an interaction between interventions and cocaine daily choice. Control rats started cocaine intake at a lower level and increased cocaine choice over time, while animals submitted to neonatal interventions started cocaine intake at higher levels of choice, with less increase in cocaine intake during the period of cocaine exposure. Rats receiving aversive stimulation during adolescence also started taking cocaine solution at higher levels. Significantly higher immobility duration and shorter latency to immobility during the forced swimming were detected in these same adolescents that received unpredictable stress, when compared to the control or handled rats, while there was no difference for rats stimulated neonatally. Therefore, early life events increase initial preference for cocaine and promote changes in its abuse pattern, according to the intensity of the event and the age of the individual at the time of the event. Moreover, adverse experiences during adolescence, but not in neonatal phases, increase the vulnerability to depressive-like behaviors during cocaine withdrawal of adult rats.

Comparison of behavioral effects of moclobemide and deprenyl during forced swimming.

The present study compared the antiimmobility effects of l-deprenyl (DEP) and moclobemide (MOC) to the classic antidepressant imipramine (IMI), using an ethological approach. To investigate the degree of MAO-B inhibition by DEP and MOC, combination of treatments of ineffective doses of phenylethylamine (PHEA) with DEP or with MOC were administered in three doses before immobility was tested in the forced-swimming paradigm. Tests were videotape recorded for analysis of the frequency and duration of the behaviors during the procedure. There was a significant, dose-dependent decrease in immobility duration and an increase in mobility duration of rats treated with IMI. Both active behaviors of climbing and swimming were equally enhanced by the tricyclic antidepressant, climbing behavior composing 75% of the mobile behaviors. The intermediate doses of the MAOIs tested, DEP 0.25 mg/kg and MOC 30 mg/kg, decreased immobility and increased mobility. The antiimmobility effect of DEP was due to longer climbing behavior while MOC enhanced swimming duration. No behavioral changes were seen with the administration of the lower and higher doses of the MAOI. Potentiation of the antiimmobility effects was observed when ineffective doses of PHEA and of DEP or MOC were administered in combination. Differences between the MAO inhibitors on the active behaviors were also observed when administered with PHEA; DEP and PHEA significantly increased climbing and MOC and PHEA increased swimming. This preclinical evaluation of selective MAO inhibitors indicates that both MAO-A and MAO-B inhibitors have antidepressant effects. However, to clearly demonstrate that these antiimmobility effects are a consequence of increased brain concentrations of any one of the several monoamines implicated in the mechanism of action of DEP or MOC should be the subject of future studies.